Compounds and methods of treating hypertension

ABSTRACT

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are adrenergic receptor α 2B  antagonists. The compounds may also bind to and antagonize adrenergic receptor α 2B . The compounds may find use in therapy, e.g., to (i) reduce blood pressure and/or (ii) promote renal blood flow and/or (iii) decrease or inhibit sodium reabsorption. The compounds may also be used to treat diseases or conditions that are, or are expected to be, responsive to a decrease in blood pressure. Use of the compounds to treat cardiovascular and renal disorders is particularly described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/444,616 filed Feb. 18, 2011, U.S. Provisional Patent ApplicationNo. 61/444,553 filed Feb. 18, 2011, and U.S. Provisional PatentApplication No. 61/444,569 filed Feb. 18, 2011, the disclosures of eachof which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Hypertension is a serious condition that can damage vital organs, suchas the heart and kidneys, and other parts of the body, such as thecentral nervous system. Individuals who have hypertension may have, orbe at risk of developing, dangerous diseases such as coronary heartdisease and kidney failure. Hypertension, which is the leadingmodifiable risk factor for cardiovascular disease mortality, causes morethan 7 million deaths every year worldwide.

Hypertension is the most common chronic medical condition in developedcountries as well as the most common indication for physician visits andprescription medication use. Hypertension affects more than 50 millionindividuals in the United States and over one billion individualsworldwide, and overall prevalence may continue to increase with theadvancing age of the population.

Unfortunately, despite the importance of blood pressure control and theavailability of multiple classes of antihypertensive agents, thetreatment of hypertension remains suboptimal. Data from the most recentNational Health and Nutrition Examination Survey demonstrate that only34% of patients with hypertension have blood pressures at theirtherapeutic goal. Additionally, it was shown that the majority ofpatients with hypertension will require two or more antihypertensiveagents to achieve their goal blood pressure. Even with optimalcompliance with multiple antihypertensive agents of different classes, asignificant fraction of patients will not be able to achieve their goalblood pressure. The overall prevalence of resistant hypertension,defined as elevated blood pressure in spite of the use of three or moreantihypertensive agents, is unknown, but small studies suggest that itranges from 5%-16% in primary care settings to greater than 50% innephrology clinics. Given data suggesting that increasing age andobesity are important risk factors for the development of resistanthypertension, it is expected that the overall prevalence of thiscondition is likely to increase due to demographic changes in thepopulation.

Systolic blood pressure tends to increase with age and systolichypertension is an important health issue, prominent in the elderly(Duprez, Am. J. Med. 121:179-184 (2008)). It has been suggested thatthis occurs as large vessels such as the aorta lose their elasticitywith age and is less able to buffer the pulsative nature of cardiacoutput. There exists a need for a treatment for patients in suchclinical setting, for example, patients with systolic hypertensionaccompanied with low diastolic pressure (Franklin et al. J. Hypertension29:1101-1108 (2011).

Metabolic syndrome is a cluster of disorders including obesity,hypertension, hypertrigleridemia, hypercholesterolemia and elevatedblood sugar. Individuals with this spectrum of disorders are atincreased risk of diabetes, heart disease and stroke. Agents capable oftreating more than one of these disorders are desirable.

Hypertensive emergencies are defined as severe elevations in bloodpressure associated with resultant organ damage (i.e. pulmonary edema,renal impairment, visual impairment, intracranial hemorrhage, orencephalopathy). The treatment of hypertensive emergencies involvesaggressive and controlled blood pressure lowering in a highly monitoredintensive care setting using intravenous blood pressure lowering agents.Therapeutic agents and method of treatment is needed to gradually lowerblood pressure and minimize damage of end organs such as the brain,kidney, heart, and eye.

The frequency of chronic kidney disease also continues to increaseworldwide as does the prevalence of end-stage renal disease. Althoughchronic kidney disease is often caused by hypertension, other factorssuch as a decrease in renal blood flow and increase in sodium retentionor reabsorption can lead to renal diseases. Increased age and diabetescan also contribute to renal disease. Especially the elderly, which area growing segment of the world population, are at increased risk forrenal disease. The presence of chronic kidney disease is also associatedwith a large increase in cardiovascular morbidity and mortality.Consequently, the identification and reduction of chronic kidney diseasehas become a vital public health priority.

Thus, there remains a need for new and useful agents that are capable of(i) reducing an individual's blood pressure and/or (ii) promoting renalblood flow and/or (iii) inhibiting or decreasing sodium reabsorption.

BRIEF SUMMARY OF THE INVENTION

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles andazepino[4,5-b]indoles are described. Compositions and kits comprisingthe compounds are also provided, as are methods of using and making thecompounds. Compounds provided herein may find use in treating a diseaseor condition that is, or is believed to be responsive to any one or moreof: (i) a decrease in blood pressure; (ii) an increase in renal bloodflow and (iii) a decrease or inhibition of sodium reabsorption. In oneaspect, compounds provided herein are selective adrenergic receptorα_(2B) antagonists that may find use in treating a disease or conditionthat is, or is believed to be responsive to any one or more of: (i) adecrease in blood pressure; (ii) an increase in renal blood flow and(iii) a decrease or inhibition of sodium reabsorption. Compoundsprovided may also find use in treating diseases and/or conditions suchas hypertension, congestive heart failure or a renal disease orcondition.

In another aspect, compounds that promote mitochondrial health andcellular viability are also described. The compounds provided herein areselective adrenergic receptor α_(2B) antagonists that may find use intreating a disease or condition that is associated with dysfunction ofmitochondria in a renal or cardiac cell. Compounds provided may alsofind use in treating diseases and/or conditions selected from the groupconsisting of acute renal failure, chronic renal failure, coronaryischemia, acute congestive heart failure, chronic congestive heartfailure, coronary artery disease, sleep apnea, respiratory distress,hypertension, and peripheral vascular disease.

In one aspect, the present invention provides methods of lowering bloodpressure in an individual in need thereof comprising administering tothe individual an effective amount of a compound of the formulae (A1),(A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1),(D2), (D3), or (D4); or a salt, solvate or N-oxide thereof; and whereinthe formulae (A1) to (D4) are as described herein. In one embodiment,the method reduces systolic blood pressure of the individual. In anotherembodiment, the method reduces diastolic blood pressure of theindividual. In another embodiment, the method reduces (i) mean arterialblood pressure, or (ii) pulse pressure, of the individual. In anotherembodiment, the method does not substantially increase heart rate of theindividual. In another embodiment, the individual has one or more riskfactors for developing high blood pressure. In another embodiment, theindividual has high blood pressure.

In another aspect, the present invention provides methods of (i)increasing renal blood flow, and/or (ii) decreasing sodium reabsorption,in an individual in need thereof comprising administering to theindividual an effective amount of a compound of the formulae (A1), (A2),(A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2),(D3), or (D4); or a salt, solvate or N-oxide thereof. In one embodiment,the method results in increase in renal blood flow. In anotherembodiment, the method results in decrease in sodium reabsorption. Inanother embodiment, the method results in increase in urine sodiumcontent and/or increase in urine volume. In another embodiment, themethod results in any one or more of: (i) reducing edema, (ii) reducingelevated blood urea nitrogen to creatinine (BUN/Cr) ratio, and (iii)decreasing creatinine levels. In another embodiment, the individual hasor is at risk of developing acute or chronic congestive heart failure,acute decompensated congestive heart failure, acute or chronic renalfailure, or acute or chronic renal failure due to renal insufficiency.

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to any one or more of: (i) adecrease in blood pressure; (ii) an increase in renal blood flow; and(iii) a decrease of sodium reabsorption, comprising administering to anindividual in need thereof an effective amount of a compound of theformulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2),(C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate or N-oxidethereof. In one embodiment, the disease or condition is hypertension. Inanother embodiment, the disease or condition is treatment-resistanthypertension. In another embodiment, the disease or condition ishypertensive emergency. In another embodiment, the disease or conditionis a cardiac or renal disease or condition. In another embodiment, thecompound is an adrenergic receptor α_(2B) antagonist. In anotherembodiment, the compound is also an adrenergic receptor α_(1B)antagonist. In another embodiment, the compound is also an adrenergicreceptor α_(1D) antagonist.

In a further aspect, the present invention provides a kit comprising (i)a compound of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4),(C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate orN-oxide thereof, or a pharmaceutically acceptable salt thereof, and (ii)instructions for use according to the methods of the invention

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless clearly indicated otherwise, the terms “a,” “an,” and the like,refer to one or more.

It is also understood and clearly conveyed by this disclosure thatreference to “the compound” or “a compound” includes and refers to anycompounds (e.g., selective adrenergic receptor α_(2B) antagonists) orpharmaceutically acceptable salt or other form thereof as describedherein.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human. The inventionmay find use in both human medicine and in the veterinary context.

As used herein, an “at risk” individual is an individual who is at riskof developing a disease or condition. An individual “at risk” may or maynot have a detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s).

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, including clinical results.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition.

As used herein, the term “effective amount” intends such amount of acompound of the invention which should be effective in a giventherapeutic form. As is understood in the art, an effective amount maybe in one or more doses, i.e., a single dose or multiple doses may berequired to achieve the desired treatment endpoint. An effective amountmay be considered in the context of administering one or moretherapeutic agents, and a single agent may be considered to be given inan effective amount if, in conjunction with one or more other agents, adesirable or beneficial result may be or is achieved. Suitable doses ofany of the co-administered compounds may optionally be lowered due tothe combined action (e.g., additive or synergistic effects) of thecompounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient, or compound which may be in a pharmaceuticallyacceptable carrier.

As used herein, by “pharmaceutically acceptable” is meant a materialthat is not biologically or otherwise undesirable, e.g., the materialmay be incorporated into a pharmaceutical composition administered to anindividual without causing significant undesirable biological effects orinteracting in a deleterious manner with any of the other components ofthe composition in which it is contained. Pharmaceutically acceptablecarriers or excipients have preferably met the required standards oftoxicological and manufacturing testing and/or are included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion,or an aluminum ion; or coordinates with an organic base. Acceptableorganic bases include ethanolamine, diethanolamine, triethanolamine andthe like. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Further examples of pharmaceutically acceptable salts includethose listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977January; 66(1):1-19. Pharmaceutically acceptable salts can be preparedin situ in the manufacturing process, or by separately reacting apurified compound of the invention in its free acid or base form with asuitable organic or inorganic base or acid, respectively, and isolatingthe salt thus formed during subsequent purification. It should beunderstood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The term “excipient” as used herein includes an inert or inactivesubstance that may be used in the production of a drug orpharmaceutical, such as a tablet containing a compound detailed herein,or a pharmaceutically acceptable salt thereof, as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

An inverse agonist is a compound that binds to a receptor and inhibitsthe activity of the receptor in the absence of an agonist. An inverseagonist requires that the receptor have some constitutive basal activityin the absence of an agonist. While an agonist increases activity of thereceptor over basal level an inverse agonist reduces receptor activitybelow basal level.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the latter example can be attached to the cyclohexenyl moietyat any available position on the ring. Cycloalkenyl is a subset ofalkenyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as norbornenyl. A more preferred cycloalkenyl is anunsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms(a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenyl groups includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C≡C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—,substituted cycloalkyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and thelike. A heterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 1 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy andthe like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. Inone variation, an aralkyl is a fused ring system where at least onecycloalkyl moiety is fused with at least one aryl moiety. A “substitutedaralkyl” refers to a residue in which an aryl moiety is attached to asubstituted alkyl residue and wherein the aralkyl group may be attachedto the parent structure at either the aryl or the alkyl residue. When anaralkyl is connected to the parent structure via the alkyl moiety, itmay also be referred to as an “alkaryl”. More particular alkaryl groupsare those having 1 to 3 carbon atoms in the alkyl moiety (a “C₁-C₃alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-cycloalkyl, —NRSO₂-substitutedcycloalkyl, —NRSO₂-aryl, —NRSO₂-substituted aryl, —NRSO₂-heteroaryl,—NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic, and—NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-aralkyl,—SO₂-substituted aralkyl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, and —SO₂-substituted heterocyclic.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Carbonylalkylenealkoxy” refers to the group —C(O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

Receptor Binding Profile

In some embodiments, compounds that bind to and are antagonists of theadrenergic receptor α_(2B), but which are not antagonists of theadrenergic receptor α_(2A), and pharmaceutically acceptable saltsthereof, are provided. The compounds may find use in therapy fordecreasing blood pressure in an individual and in treating diseases orconditions which are responsive to (i) a decrease in blood pressureand/or (ii) an increase in renal blood flow and/or (iii) a decrease orinhibition of sodium reabsorption or sodium retention. Thus, anindividual who has a disease or condition that is responsive to (i) adecrease in blood pressure and/or (ii) an increase in renal blood flowand/or (iii) a decrease or inhibition of sodium reabsorption or sodiumretention will experience one or more beneficial or desirable resultsupon administration of a compound provided herein, or pharmaceuticallyacceptable salt thereof. In one aspect, the beneficial or desirableresult is a reduction in the individual's mean arterial blood pressurefor a period of time following administration of the compound orpharmaceutically acceptable salt thereof. In another aspect, thebeneficial or desirable result is a reduction in the individual'ssystolic blood pressure for a period of time following administration ofthe compound or pharmaceutically acceptable salt thereof. In a furtheraspect, the beneficial or desirable result is an increase in renal bloodflow (e.g., by altering the vascular tone of renal efferent and afferentarterioles) for a period of time following administration of thecompound or pharmaceutically acceptable salt thereof. In another aspect,the beneficial or desirable result is a decrease or inhibition in sodiumreabsorption (e.g., thereby exerting a natriuretic and diuretic effect)for a period of time following administration of the compound orpharmaceutically acceptable salt thereof. In another aspect, thebeneficial or desirable result is an increase in urine sodium and/orurine volume for a period of time following administration of thecompound or pharmaceutically acceptable salt thereof. In one variation,the compounds may find use in therapy in treating diseases or conditionswhich are responsive to (i) a decrease in blood pressure and (ii) anincrease in renal blood flow. In one variation, the compounds my finduse in therapy in treating diseases or conditions which are responsiveto (i) a decrease in blood pressure and (ii) a decrease or inhibition ofsodium reabsorption. In one variation, the compounds may find use intreating diseases or conditions which are responsive to (i) an increasein renal blood flow and (ii) a decrease or inhibition of sodiumreabsorption. In one variation, the compounds may find use in therapy intreating diseases or conditions which are responsive to (i) a decreasein blood pressure and (ii) an increase in renal blood flow and (iii) adecrease or inhibition of sodium reabsorption.

Compounds that bind to and are antagonists of the adrenergic receptorα_(2B) should reduce an individual's blood pressure. However, compoundsthat antagonize the adrenergic receptor α_(2A) in some instances mayactually increase an individual's blood pressure. Thus, compounds thatantagonize the adrenergic receptor α_(2B) but do not antagonize theadrenergic receptor α_(2A) (compounds referred to herein as “selectiveadrenergic receptor α_(2B) antagonists”) are desirable agents intherapy. Selective adrenergic receptor α_(2B) antagonists find furtheruse in therapy of cardiovascular and renal indications. The selectiveadrenergic receptor α_(2B) antagonists provided herein (i) bind to andare antagonists of the adrenergic receptor α_(2B), and (ii) are notantagonists of the adrenergic receptor α_(2A).

The selective adrenergic receptor α_(2B) antagonists may in somevariations also bind to and be agonists of the adrenergic receptorα_(2A). The selective adrenergic receptor α_(2B) antagonists may also beused in conjunction with other agents that are agonists of theadrenergic receptor α_(2A).

The selective adrenergic receptor α_(2B) antagonists may in somevariations also bind to and be antagonists of the adrenergic receptorα_(1B). The selective adrenergic receptor α_(2B) antagonists may also beused in conjunction with other agents that are antagonists of theadrenergic receptor α_(1B).

The selective adrenergic receptor α_(2B) antagonists may in somevariations also bind to and be antagonists of the adrenergic receptorα_(1D). The selective adrenergic receptor α_(2B) antagonists may also beused in conjunction with other agents that are antagonists of theadrenergic receptor α_(1D).

The selective adrenergic receptor α_(2B) antagonists may in somevariations both (i) bind to and be agonists of the adrenergic receptorα_(2A) and (ii) bind to and be antagonists of the adrenergic receptorα_(1B) and/or α_(1D).

In one variation, a selective adrenergic receptor α_(2B) antagonistexhibits (i) equal to or greater than about 60% inhibition of α_(2B)ligand binding at 0.03 μM and antagonist activity to adrenergic receptorα_(2B) and (ii) equal to or less than about 30% inhibition of α_(2A)ligand binding at 0.1 μM and absence of antagonist activity toadrenergic receptor α_(2A). In one variation, a selective adrenergicreceptor α_(2B) antagonist exhibits (i) equal to or greater than aboutany one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about60% and about 90%, between about 70% and about 90%, or between about 80%and about 100% inhibition of α_(2B) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(2B), and (ii) equal to orless than about any one of 30%, 25%, 20%, 15%, 10%, or 5%, or betweenabout 0% and about 30%, between about 10% and about 30%, or betweenabout 20% and about 30% inhibition of α_(2A) ligand binding at 0.1 μMand absence of antagonist activity to adrenergic receptor α_(2A). In onevariation, a selective adrenergic receptor α_(2B) antagonist exhibits(i) equal to or greater than about 60% inhibition of α_(2B) ligandbinding at 0.1 μM and antagonist activity to adrenergic receptor α_(2B)and (ii) equal to or less than about 30% inhibition of α_(2A) ligandbinding at 0.1 μM and absence of antagonist activity to adrenergicreceptor α_(2A). In one variation, a selective adrenergic receptorα_(2B) antagonist exhibits (i) equal to or greater than about any one of60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% andabout 90%, between about 70% and about 90%, or between about 80% andabout 100% inhibition of α_(2B) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(2B), and (ii) equal to or less thanabout any one of 30%, 25%, 20%, 15%, 10%, or 5%, or between about 0% andabout 30%, between about 10% and about 30%, or between about 20% andabout 30% inhibition of α_(2A) ligand binding at 0.1 μM and absence ofantagonist activity to adrenergic receptor α_(2A). It is understood andclearly conveyed herein that a selective adrenergic receptor α_(2B)antagonist can exhibit any of the adrenergic receptor α_(2B) bindingprofiles described herein in combination with any of the adrenergicreceptor α_(2A) binding profiles described herein, as if each and everycombination were listed separately. For example, a selective adrenergicreceptor α_(2B) antagonist may exhibit (i) equal to or greater thanabout 65% inhibition of α_(2B) ligand binding at 0.03 μM and antagonistactivity to adrenergic receptor α_(2B), and (ii) equal to or less thanabout 25% inhibition of α_(2A) ligand binding at 0.1 μM and absence ofantagonist activity to adrenergic receptor α_(2A).

In one variation, a selective adrenergic receptor α_(2B) antagonistexhibits (i) equal to or greater than about 60% inhibition of α_(2B)ligand binding at 0.03 μM and antagonist activity to adrenergic receptorα_(2B) and (ii) equal to or less than about 30% inhibition of α_(2A)ligand binding at 0.03 μM and absence of antagonist activity toadrenergic receptor α_(2A). In one variation, a selective adrenergicreceptor α_(2B) antagonist exhibits (i) equal to or greater than aboutany one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about60% and about 90%, between about 70% and about 90%, or between about 80%and about 100% inhibition of α_(2B) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(2B), and (ii) equal to orless than about any one of 30%, 25%, 20%, 15%, 10%, or 5%, or betweenabout 0% and about 30%, between about 10% and about 30%, or betweenabout 20% and about 30% inhibition of α_(2A) ligand binding at 0.03 μMand absence of antagonist activity to adrenergic receptor α_(2A). In onevariation, a selective adrenergic receptor α_(2B) antagonist exhibits(i) equal to or greater than about 60% inhibition of α_(2B) ligandbinding at 0.1 μM and antagonist activity to adrenergic receptor α_(2B)and (ii) equal to or less than about 30% inhibition of α_(2A) ligandbinding at 0.03 μM and absence of antagonist activity to adrenergicreceptor α_(2A). In one variation, a selective adrenergic receptorα_(2B) antagonist exhibits (i) equal to or greater than about any one of60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about 60% andabout 90%, between about 70% and about 90%, or between about 80% andabout 100% inhibition of α_(2B) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(2B), and (ii) equal to or less thanabout any one of 30%, 25%, 20%, 15%, 10%, or 5%, or between about 0% andabout 30%, between about 10% and about 30%, or between about 20% andabout 30% inhibition of α_(2A) ligand binding at 0.03 μM and absence ofantagonist activity to adrenergic receptor α_(2A). It is understood andclearly conveyed herein that a selective adrenergic receptor α_(2B)antagonist can exhibit any of the adrenergic receptor α_(2B) bindingprofiles described herein in combination with any of the adrenergicreceptor α_(2A) binding profiles described herein, as if each and everycombination were listed separately. For example, a selective adrenergicreceptor α_(2B) antagonist may exhibit (i) equal to or greater thanabout 65% inhibition of α_(2B) ligand binding at 0.03 μM and antagonistactivity to adrenergic receptor α_(2B), and (ii) equal to or less thanabout 25% inhibition of α_(2A) ligand binding at 0.03 μM and absence ofantagonist activity to adrenergic receptor α_(2A).

In another variation, a selective adrenergic receptor α_(2B) antagonisthas a Ki ratio of α_(2A) to α_(2B) that is greater than about any one of5 or 15 or 50. Ki is the binding affinity from the Cheng-Prusoffequation: Ki=IC₅₀/(1+[S]/Kd), wherein [S] is the concentration of theradioligand and Kd is dissociation constant (affinity) of theradioligand for the protein (Cheng, Y., Prusoff, W. H., Biochem.Pharmacol. 22:3099-3108, 1973). It is understood that the Ki ratio ofα_(2A) to α_(2B) may be combined with any binding and/or other activityprofile details described herein for selective adrenergic receptorα_(2B) antagonists the same as if each were specifically andindividually listed. For example, in one variation, a selectiveadrenergic receptor α_(2B) antagonist may exhibit (i) equal to orgreater than about 65% inhibition of α_(2B) ligand binding at 0.03 μMand antagonist activity to adrenergic receptor α_(2B), and (ii) equal toor less than about 25% inhibition of α_(2A) ligand binding at 0.1 μM andabsence of antagonist activity to adrenergic receptor α_(2A); and a Kiratio of α_(2A) to α_(2B) that is greater than about any one of 5 or 15or 50.

The selective adrenergic receptor α_(2B) antagonists may in somevariations also bind to and be antagonists of the adrenergic receptorα_(1B). In one variation, the selective adrenergic receptor α_(2B)antagonists may exhibit (i) equal to or greater than about 60%inhibition of α_(2B) ligand binding at 0.03 μM and antagonist activityto adrenergic receptor α_(2B), (ii) equal to or less than about 30%inhibition of α_(2A) ligand binding at 0.1 μM and absence of antagonistactivity to adrenergic receptor α_(2A), and (iii) equal to or greaterthan about 60% inhibition of α_(1B) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(1B). In one variation, theselective adrenergic receptor α_(2B) antagonists may exhibit (i) equalto or greater than about 60% inhibition of α_(2B) ligand binding at 0.03μM and antagonist activity to adrenergic receptor α_(2B), (ii) equal toor less than about 30% inhibition of α_(2A) ligand binding at 0.1 μM andabsence of antagonist activity to adrenergic receptor α_(2A), and (iii)equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%,90%, or 95%, or between about 60% and 90%, between about 70% and 90%, orbetween about 80% and about 100% inhibition of α_(1B) ligand binding at0.03 μM and antagonist activity to adrenergic receptor α_(1B). In onevariation, the selective adrenergic receptor α_(2B) antagonists mayexhibit (i) equal to or greater than about 60% inhibition of α_(2B)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(2B), (ii) equal to or less than about 30% inhibition of α_(2A) ligandbinding at 0.1 μM and absence of antagonist activity to adrenergicreceptor α_(2A), and (iii) equal to or greater than about 60% inhibitionof α_(1B) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(1B). In one variation, the selective adrenergic receptorα_(2B) antagonists may exhibit (i) equal to or greater than about 60%inhibition of α_(2B) ligand binding at 0.03 μM and antagonist activityto adrenergic receptor α_(2B), (ii) equal to or less than about 30%inhibition of α_(2A) ligand binding at 0.1 μM and absence of antagonistactivity to adrenergic receptor α_(2A), and (iii) equal to or greaterthan about 60% inhibition of α_(1B) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(1B). In one variation, theselective adrenergic receptor α_(2B) antagonists may exhibit (i) equalto or greater than about 60% inhibition of α_(2B) ligand binding at 0.03μM and antagonist activity to adrenergic receptor α_(2B), (ii) equal toor less than about 30% inhibition of α_(2A) ligand binding at 0.1 μM andabsence of antagonist activity to adrenergic receptor α_(2A), and (iii)equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%,90%, or 95%, or between about 60% and 90%, between about 70% and 90%, orbetween about 80% and about 100% inhibition of α_(1B) ligand binding at0.1 μM and antagonist activity to adrenergic receptor α_(1B). It isunderstood and clearly conveyed herein that a selective adrenergicreceptor α_(2B) antagonist can exhibit any of the adrenergic receptorα_(2B) binding profiles described herein in combination with any of theadrenergic receptor α_(2A) binding profiles described herein and any ofthe adrenergic receptor α_(1B) binding profiles, as if each and everycombination were listed separately. For example, a selective adrenergicreceptor α_(2B) antagonist may exhibit (i) equal to or greater thanabout 65% inhibition of α_(2B) ligand binding at 0.03 μM and antagonistactivity to adrenergic receptor α_(2B), (ii) equal to or less than about25% inhibition of α_(2A) ligand binding at 0.1 μM and absence ofantagonist activity to adrenergic receptor α_(2A), and (iii) equal to orgreater than about 65% inhibition of α_(1B) ligand binding at 0.03 μMand antagonist activity to adrenergic receptor α_(1B). The selectiveadrenergic receptor α_(2B) antagonists may also be used in conjunctionwith other agents that antagonize the adrenergic receptor α_(1B).Administration in conjunction with another compound includesadministration in the same or different composition, eithersequentially, simultaneously, or continuously.

The selective adrenergic receptor α_(2B) antagonists may in somevariations also bind to and be antagonists of the adrenergic receptorα_(1D). In one variation, the selective adrenergic receptor α_(2B)antagonists may exhibit (i) equal to or greater than about 60%inhibition of α_(2B) ligand binding at 0.03 μM and antagonist activityto adrenergic receptor α_(2B), (ii) equal to or less than about 30%inhibition of α_(2A) ligand binding at 0.1 μM and absence of antagonistactivity to adrenergic receptor α_(2A), and (iii) equal to or greaterthan about 60% inhibition of α_(1D) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(1D). In another variation,the selective adrenergic receptor α_(2B) antagonists may exhibit (i)equal to or greater than about 60% inhibition of α_(2B) ligand bindingat 0.03 μM and antagonist activity to adrenergic receptor α_(2B), (ii)equal to or less than about 30% inhibition of α_(2A) ligand binding at0.1 μM and absence of antagonist activity to adrenergic receptor α_(2A),(iii) equal to or greater than about 60% inhibition of α_(1B) ligandbinding at 0.03 μM and antagonist activity to adrenergic receptor α_(1B)and (iv) equal to or greater than about 60% inhibition of α_(1D) ligandbinding at 0.03 μM and antagonist activity to adrenergic receptorα_(1D). In one variation, the selective adrenergic receptor α_(2B)antagonists may exhibit (i) equal to or greater than about 60%inhibition of α_(2B) ligand binding at 0.03 μM and antagonist activityto adrenergic receptor α_(2B), (ii) equal to or less than about 30%inhibition of α_(2A) ligand binding at 0.1 μM and absence of antagonistactivity to adrenergic receptor α_(2A), and (iii) equal to or greaterthan about any one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, orbetween about 60% and 90%, between about 70% and 90%, or between about80% and about 100% inhibition of α_(1D) and/or α_(1B) ligand binding at0.03 μM and antagonist activity to adrenergic receptor α_(1D) and/orα_(1B). In one variation, the selective adrenergic receptor α_(2B)antagonists may exhibit (i) equal to or greater than about 60%inhibition of α_(2B) ligand binding at 0.1 μM and antagonist activity toadrenergic receptor α_(2B), (ii) equal to or less than about 30%inhibition of α_(2A) ligand binding at 0.1 μM and absence of antagonistactivity to adrenergic receptor α_(2A), and (iii) equal to or greaterthan about 60% inhibition of α_(1B) and/or α_(1D) ligand binding at 0.1μM and antagonist activity to adrenergic receptor α_(1B) and/or α_(1D).In one variation, the selective adrenergic receptor α_(2B) antagonistsmay exhibit (i) equal to or greater than about 60% inhibition of α_(2B)ligand binding at 0.03 μM and antagonist activity to adrenergic receptorα_(2B), (ii) equal to or less than about 30% inhibition of α_(2A) ligandbinding at 0.1 μM and absence of antagonist activity to adrenergicreceptor α_(2A), and (iii) equal to or greater than about 60% inhibitionof α_(1B) and/or α_(1D) ligand binding at 0.1 μM and antagonist activityto adrenergic receptor α_(1B) and/or α_(1D). In one variation, theselective adrenergic receptor α_(2B) antagonists may exhibit (i) equalto or greater than about 60% inhibition of α_(2B) ligand binding at 0.03μM and antagonist activity to adrenergic receptor α_(2B), (ii) equal toor less than about 30% inhibition of α_(2A) ligand binding at 0.1 μM andabsence of antagonist activity to adrenergic receptor α_(2A), and (iii)equal to or greater than about any one of 60%, 65%, 70%, 75%, 80%, 85%,90%, or 95%, or between about 60% and 90%, between about 70% and 90%, orbetween about 80% and about 100% inhibition of α_(1B) and/or α_(1D)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(1B) and/or α_(1D). It is understood and clearly conveyed herein thata selective adrenergic receptor α_(2B) antagonist can exhibit any of theadrenergic receptor α_(2B) binding profiles described herein incombination with any of the adrenergic receptor α_(2A) binding profilesdescribed herein and any of the adrenergic receptor α_(1B) and/or α_(1D)binding profiles, as if each and every combination were listedseparately. For example, a selective adrenergic receptor α_(2B)antagonist may exhibit (i) equal to or greater than about 65% inhibitionof α_(2B) ligand binding at 0.03 μM and antagonist activity toadrenergic receptor α_(2B), (ii) equal to or less than about 25%inhibition of α_(2A) ligand binding at 0.1 μM and absence of antagonistactivity to adrenergic receptor α_(2A), and (iii) equal to or greaterthan about 65% inhibition of α_(1D) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(1D). The selectiveadrenergic receptor α_(2B) antagonists may also be used in conjunctionwith other agents that antagonize the adrenergic receptor α_(1D).Administration in conjunction with another compound includesadministration in the same or different composition, eithersequentially, simultaneously, or continuously.

In some instances, compounds provided herein bind to and are antagonistsof adrenergic receptor α_(2B) and may also be antagonists for theadrenergic receptor α_(2A). In such instances, it is preferable that thecompound is more potent at inhibiting the adrenergic receptor α_(2B)compared to the adrenergic receptor α_(2A). In one variation, thecompound inhibit both the adrenergic receptor α_(2B) and the adrenergicreceptor α_(2A), and wherein the compound has limited of no brainbioavailability and so cannot easily activate adrenergic α_(2A)receptors in the brain. In one variation, the compound inhibit both theadrenergic receptor α_(2B) and the adrenergic receptor α_(2A), andwherein the compound has brain bioavailability. In some other instances,compounds provided herein bind to and are antagonists of adrenergicreceptor α_(2B) and may be inverse agonists for the adrenergic receptorα_(2A). In some embodiments, the compound (1) binds to and is anantagonist of adrenergic receptor α_(2B), and (2) binds to and is anantagonist and/or inverse agonist of the adrenergic receptor α_(2A). Insome embodiments, the compound (1) binds to and is an antagonist ofadrenergic receptor α_(2B), (2) binds to and is an antagonist and/orinverse agonist of the adrenergic receptor α_(2A), and (3) binds to andis antagonist of the adrenergic receptor α_(1B) and/or the adrenergicreceptor α_(1D). It is understood and clearly conveyed herein that anadrenergic receptor α_(2B) antagonist can exhibit any of the adrenergicreceptor α_(2B) binding profiles (in terms of % inhibition at a givenconcentration and/or in terms of K_(i)) described herein in combinationwith any of the adrenergic receptor α_(1B) and/or α_(1D) bindingprofiles, as if each and every combination were listed separately.

The binding properties to adrenergic receptors of compounds disclosedherein may be assessed by methods known in the art, such as competitivebinding assays. In one variation, compounds are assessed by the bindingassays detailed herein. In one variation, inhibition of binding of aligand to a receptor is measured by the assays described herein. Inanother variation, inhibition of binding of a ligand is measured in anassay known in the art.

Functional Assay Profile

Antagonist activity to the adrenergic receptor α_(2B) receptor may beassessed by methods known in the art, such as standard α_(2B) receptorcell membrane-based or intact cell-based activity assays. For example,the GTPγS binding or Aequorin-based assays may be used. In onevariation, the selective adrenergic receptor α_(2B) antagonists exhibitan IC₅₀ value equal to or less than about any one of 100 nM, 30 nM or 10nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay)) in an α_(2B) antagonist assay. In onevariation, a selective adrenergic receptor α_(2B) antagonist exhibits anIC₅₀ value in an α_(2B) antagonist assay equal to or less than about 10nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay)) in an α_(2B) antagonist assay. In onevariation, a selective adrenergic receptor α_(2B) antagonist exhibits anIC₅₀ value in an α_(2B) antagonist assay equal to or less than about anyone of 100 nM, 30 nM or 10 nM at a concentration of oxymetazolinecorresponding to its EC₈₀ concentration as obtained by assay protocolsdescribed herein. In one variation, a selective adrenergic receptorα_(2B) antagonist exhibits an IC₅₀ value in an α_(2B) antagonist assayequal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of oxymetazoline between about 50 nM and about 5000 nM. Inone variation, a selective adrenergic receptor α_(2B) antagonistexhibits an IC₅₀ value in an α_(2B) antagonist assay equal to or lessthan about any one of 100 nM, 30 nM or 10 nM at a concentration of about480 nM oxymetazoline. In one variation, a selective adrenergic receptorα_(2B) antagonist exhibits an IC₅₀ value in an α_(2B) antagonist assayequal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of guanfacine between about 50 nM and about 5000 nM. Inone variation, a selective adrenergic receptor α_(2B) antagonistexhibits an IC₅₀ value in an α_(2B) antagonist assay equal to or lessthan about any one of 100 nM, 30 nM or 10 nM at a concentration of about500 nM guanfacine, which in a particular variation is 504 nM guanfacine.

The absence of antagonist activity to the adrenergic receptor α_(2A) maybe assessed by methods known in the art, such as standard α_(2A)receptor intact cell-based activity assays. For example, theAequorin-based assay may be used. It is understood and clearly conveyedthat absence of antagonist activity to the adrenergic receptor α_(2A)intends activity that is sufficiently reduced, but not necessarilyeliminated or undetectable, at the adrenergic receptor α_(2A). In onevariation, a compound will exhibit an undetectable amount of antagonistactivity to the adrenergic receptor α_(2A). In another variation, acompound will lack antagonist activity to the adrenergic receptor α_(2A)if it exhibits an IC₅₀ value in an α_(2A) antagonist assay that isgreater than about any one of 50 nM, 100 nM or 200 nM at a givenconcentration of agonist (e.g., concentration corresponding to EC₈₀ ofUK14304). In one variation, the adrenergic receptor α_(2A) exhibits anIC₅₀ value in an α_(2A) antagonist assay that is greater than about 200nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of UK14304). In one variation, a selectiveadrenergic receptor α_(2B) antagonist exhibits an IC₅₀ value in anα_(2A) antagonist assay greater than about any one of 50 nM, 100 nM or200 nM at a concentration of UK14304 corresponding to its EC₈₀concentration as obtained by assay protocols described herein. In onevariation, a selective adrenergic receptor α_(2B) antagonist exhibits anIC₅₀ value in an α_(2A) antagonist assay greater than about any one of50 nM, 100 nM or 200 nM at a concentration of UK14304 between about 0.4nM and about 40 nM. In one variation, a selective adrenergic receptorα_(2B) antagonists exhibits an IC₅₀ value in an α_(2A) antagonist assaygreater than about any one of 50 nM, 100 nM or 200 nM at a concentrationof about 5 nM UK14304, which in a particular variation is 4.57 nMUK14304. Alternatively, a compound that does not bind the α_(2A)receptor will be neither an agonist nor antagonist of the α_(2A)receptor.

In some variations, regardless of IC₅₀ values obtained from α_(2B) andα_(2A) assays, a compound may nonetheless be a selective adrenergicreceptor α_(2B) antagonist if it exhibits a Ki ratio of α_(2A) to α_(2B)that is higher than about any one of 5, 10, or 15. For example, where acompound exhibits an IC₅₀ value between about 50-100 nM in an α_(2B)antagonist assay at a given concentration of agonist (e.g.,concentration corresponding to EC₈₀ of oxymetazoline) and an IC₅₀ valuebetween about 50 and 100 nM in an α_(2A) antagonist assay at a givenconcentration of agonist (e.g., concentration corresponding to EC₈₀ ofUK14304), the compound is considered, in one variation, a selectiveadrenergic receptor α_(2B) antagonist if it exhibits a Ki ratio ofα_(2A) to α_(2B) higher than about any one of 5, 10, or 15.

Antagonist activity to adrenergic receptor α_(1B) may be assessed bymethods known in the art, such as standard α_(1B) receptor intactcell-based activity assays, including the Aequorin-based assay. In onevariation, a selective adrenergic receptor α_(2B) antagonist will alsoantagonize the adrenergic receptor α_(1B) and exhibit an IC₅₀ valueequal to or less than about any one of 100 nM or 30 nM or 10 nM at agiven concentration of agonist (e.g., concentration corresponding toEC₈₀ of cirazoline) in an adrenergic receptor α_(1B) antagonist assay.In one variation, a selective adrenergic receptor α_(2B) antagonist willalso antagonize the adrenergic receptor α_(1B) and exhibit an IC₅₀ valueequal or less than about 10 nM at a given concentration of agonist(e.g., concentration corresponding to EC₈₀ of cirazoline) in anadrenergic receptor α_(1B) antagonist assay. In one variation, theselective adrenergic receptor α_(2B) antagonists exhibit an IC₅₀ valuein an α_(1B) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a concentration of cirazoline corresponding to itsEC₈₀ concentration as obtained by assay protocols described herein. Inone variation, the selective adrenergic receptor α_(2B) antagonistsexhibit an IC₅₀ value in an α_(1B) antagonist assay equal to or lessthan about any one of 100 nM, 30 nM or 10 nM at a concentration ofcirazoline between about 2.3 nM and about 230 nM. In one variation, theselective adrenergic receptor α_(2B) antagonists exhibit an IC₅₀ valuein an α_(1B) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, whichin a particular variation is 23.56 nM cirazoline.

Antagonist activity to adrenergic receptor α_(1D) may be assessed bymethods known in the art, such as standard α_(1D) receptor intactcell-based activity assays, including the Aequorin-based assay. In onevariation, a selective adrenergic receptor α_(2B) antagonist will alsoantagonize the adrenergic receptor α_(1D) and exhibit an IC₅₀ valueequal to or less than about any one of 100 nM or 30 nM or 10 nM at agiven concentration of agonist (e.g., concentration corresponding toEC₈₀ of cirazoline) in an adrenergic receptor α_(1D) antagonist assay.In one variation, a selective adrenergic receptor α_(2B) antagonist willalso antagonize the adrenergic receptor α_(1D) and exhibit an IC₅₀ valueequal or less than about 10 nM at a given concentration of agonist(e.g., concentration corresponding to EC₈₀ of cirazoline) in anadrenergic receptor α_(1D) antagonist assay. In one variation, theselective adrenergic receptor α_(2B) antagonists exhibit an IC₅₀ valuein an α_(1D) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a concentration of cirazoline corresponding to itsEC₈₀ concentration as obtained by assay protocols described herein. Inone variation, the selective adrenergic receptor α_(2B) antagonistsexhibit an IC₅₀ value in an α_(1D) antagonist assay equal to or lessthan about any one of 100 nM, 30 nM or 10 nM at a concentration ofcirazoline between about 2.3 nM and about 230 nM. In one variation, theselective adrenergic receptor α_(2B) antagonists exhibit an IC₅₀ valuein an α_(1D) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, whichin a particular variation is 23.56 nM cirazoline.

In one variation, the selective adrenergic receptor α_(2B) antagonistsexhibit (i) equal to or greater than about 60% inhibition of α_(2B)ligand binding at 0.03 μM and an IC₅₀ value in an α_(2B) antagonistassay equal to or less than about any one of 100 nM, 30 nM or 10 nM at agiven concentration of agonist (e.g., concentration corresponding toEC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγSassay)), and (ii) equal to or less than about 30% inhibition of α_(2A)ligand binding at 0.1 μM and an IC₅₀ value in an α_(2A) antagonist assaythat is greater than about any one of 50 nM, 100 nM or 200 nM at a givenconcentration of agonist (e.g., concentration corresponding to EC₈₀ ofUK14304). In some variations, the selective adrenergic receptor α_(2B)antagonists exhibit (i) equal to or greater than about 60% inhibition ofα_(2B) ligand binding at 0.03 μM and an IC₅₀ value in an α_(2B)antagonist assay equal to or less than about any one of 100 nM, 30 nM or10 nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay)), and (ii) equal to or less than about 30%inhibition of α_(2A) ligand binding at 0.1 μM and an IC₅₀ value in anα_(2A) antagonist assay that is greater than about any one of 50 nM, 100nM or 200 nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of UK14304), and (iii) equal to or greater thanabout 60% inhibition of α_(1B) ligand binding at 0.03 μM and an IC₅₀value in an α_(1B) antagonist assay equal or less than about any one of100 nM or 30 nM or 10 nM at a given concentration of agonist (e.g.,concentration corresponding to EC₈₀ of cirazoline). In some variations,the selective adrenergic receptor α_(2B) antagonists exhibit (i) equalto or greater than about 60% inhibition of α_(2B) ligand binding at 0.03μM and an IC₅₀ value in an α_(2B) antagonist assay equal to or less thanabout any one of 100 nM, 30 nM or 10 nM at a given concentration ofagonist (e.g., concentration corresponding to EC₈₀ of oxymetazoline (forAequorin assay) or guanfacine (for GTPγS assay)), and (ii) equal to orless than about 30% inhibition of α_(2A) ligand binding at 0.1 μM and anIC₅₀ value in an α_(2A) antagonist assay that is greater than about anyone of 50 nM, 100 nM or 200 nM at a given concentration of agonist(e.g., concentration corresponding to EC₈₀ of UK14304), and (iii) equalto or greater than about 60% inhibition of α_(1D) ligand binding at 0.03μM and an IC₅₀ value in an α_(1D) antagonist assay equal or less thanabout any one of 100 nM or 30 nM or 10 nM at a given concentration ofagonist (e.g., concentration corresponding to EC₈₀ of cirazoline). Insome variations, the selective adrenergic receptor α_(2B) antagonistsexhibit (i) equal to or greater than about 60% inhibition of α_(2B)ligand binding at 0.03 μM and an IC₅₀ value in an α_(2B) antagonistassay equal to or less than about any one of 100 nM, 30 nM or 10 nM at agiven concentration of agonist (e.g., concentration corresponding toEC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγSassay)), and (ii) equal to or less than about 30% inhibition of α_(2A)ligand binding at 0.1 μM and an IC₅₀ value in an α_(2A) antagonist assaythat is greater than about any one of 50 nM, 100 nM or 200 nM at a givenconcentration of agonist (e.g., concentration corresponding to EC₈₀ ofUK14304), (iii) equal to or greater than about 60% inhibition of α_(1B)ligand binding at 0.03 μM and an IC₅₀ value in an α_(1B) antagonistassay equal or less than about any one of 100 nM or 30 nM or 10 nM at agiven concentration of agonist (e.g., concentration corresponding toEC₈₀ of cirazoline); and (iv) equal to or greater than about 60%inhibition of α_(1D) ligand binding at 0.03 μM and an IC₅₀ value in anα_(1D) antagonist assay equal or less than about any one of 100 nM or 30nM or 10 nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of cirazoline).

In another variation, the selective adrenergic receptor α_(2B)antagonists exhibit (i) equal to or greater than about 60% inhibition ofα_(2B) ligand binding at 0.03 μM and an IC₅₀ value in an α_(2B)antagonist assay equal to or less than any about one of 100 nM, 30 nM or10 nM at a given concentration of agonist (e.g., concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay)), and (ii) binding to and agonist activityto adrenergic receptor α_(2A.)

In another variation, the adrenergic receptor α_(2B) antagonists exhibit(i) equal to or greater than about 60% inhibition of α_(2B) ligandbinding at 0.03 μM and an IC₅₀ value in an α_(2B) antagonist assay equalto or less than any about one of 100 nM, 30 nM or 10 nM at a givenconcentration of agonist (e.g., concentration corresponding to EC₈₀ ofoxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay)), and(ii) greater than or equal to about 50% inhibition of α_(2A) ligandbinding at 0.1 μM and IC₅₀ value in an adrenergic receptor α_(2A)antagonist assay equal to or less than about any one of 100 nM, 30 nM or10 nM at a concentration of UK14304 (for Aequorin assay) correspondingto its EC₈₀ concentration obtained by assay protocols described herein.

It is understood and clearly conveyed herein that compounds providedherein, including selective adrenergic receptor α_(2B) antagonistsprovided herein can exhibit any of the binding profiles and any of theantagonist or agonist activity profiles detailed herein, the same as ifeach and every combination were individually listed. For example, in onevariation, the selective adrenergic receptor α_(2B) antagonists exhibit(i) greater than about 65% inhibition of α_(2B) ligand binding at 0.03μM and an IC₅₀ value in an α_(2B) antagonist assay equal to or less thanabout 10 nM at a concentration of oxymetazoline corresponding to itsEC₈₀ concentration as obtained by assay protocols described herein, and(ii) less than about 25% inhibition of α_(2A) ligand binding at 0.1 μMand an IC₅₀ value in an α_(2A) antagonist assay that is greater than 200nM at a concentration of UK14304 corresponding to its EC₈₀ concentrationas obtained by assay protocols described herein, and (iii) equal to orgreater than about 60% inhibition of α_(1B) ligand binding at 0.03 μMand an IC₅₀ value in an α_(1B) antagonist assay equal or less than 10 nMat a concentration of cirazoline corresponding to its EC₈₀ concentrationas obtained by assay protocols described herein. In one aspect, such acompound will also exhibit a Ki ratio of α_(2A) to α_(2B) that isgreater than about any one of 5 or 15 or 50.

Medical Use

Without being bound by theory, it is believed that the compoundsprovided herein are capable of (i) reducing blood pressure and/or (ii)promoting renal blood flow and/or (iii) decreasing or inhibiting sodiumreabsorption. In some embodiments, the compounds are adrenergic receptorα_(2B) antagonists (e.g., selective adrenergic receptor α_(2B)antagonists). In some embodiments, it is believed that the selectiveadrenergic receptor α_(2B) antagonists provided herein are capable of(i) reducing blood pressure and/or (ii) promoting renal blood flowand/or (iii) decreasing or inhibiting sodium reabsorption withoutconcomitantly antagonizing the α_(2A) receptor, which would reduce orpotentially eliminate the beneficial blood pressure lowering and renaleffects modulated by antagonizing α_(2B). Furthermore, the selectiveadrenergic receptor α_(2B) antagonists provided herein may be capable ofdecreasing blood pressure sensitivity to salt, decreasing sodiumretention, decreasing vasoconstriction in small arteries and veins,increasing insulin secretion, increasing basal metabolic rate,decreasing platelet aggregation and/or enhancing mitochondrial function.However, in certain cases where the compound has strong antagonistactivities against adrenergic receptor α_(2B) and/or adrenergic receptorα_(1B), some antagonist activity against adrenergic receptor α_(2A) maybe tolerated and even beneficial.

Compounds provided herein may be capable of mediating control of therenal function. Adrenergic α_(2B) receptors are located within thekidney. Regard et al. (Cell 2008; 135:561) have demonstrated that thegene for the adrenergic α_(2B) receptor is most abundantly expressed inthe kidney. Meister et al. (J. Pharmacol. Exp. Therapeutics 1994;268:1605) have shown by in situ hybridization that expressionpredominates in the medulla outer stripe with extensions into thecortical S3 segment of the proximal tubules. Adrenergic α_(2B) receptorantagonists provided herein may be capable of disrupting sodiumreabsorption resulting in natriuresis and diuresis. Methods to determineeffects of adrenergic α_(2B) antagonists on renal function in a rabbitmodel of hypertension have been described by Burke et al. (J Hypertens29:945-952).

In addition to reducing blood pressure, compounds disclosed herein,including adrenergic α_(2B) antagonists, are capable of a reduction inblood volume that might result from diueresis and/or the movement offluid from the vascular space to the extravascular space. Reduction ofblood volume results in increase in hematocrit levels which can bemeasured by methods known in the art, for example by estimation oferythrocyte volume_fraction Characterization of the effect of α_(2B)antagonists on renal function are determined by measuring urine volume,urine sodium and urine potassium using methods described by Burke et al.(Effects of chronic sympatho-inhibition on renal excretory function inrenovascular hypertension Sandra L. Burke, Roger G. Evans and GeoffreyA. Head. Journal of Hypertens 29:945-952 (2011).

The compounds detailed herein are expected to find use in therapy,particularly in cardiac and renal diseases and conditions, in additionto hypertension and other conditions in which a (i) reduction in bloodpressure and/or (ii) increase in renal blood flow and/or (iii) decreasein sodium reabsorption would be beneficial. In the methods providedherein, an effective amount of a compound detailed herein isadministered to an individual. Methods of using compounds as describedherein to (i) reduce blood pressure and/or (ii) promote renal blood flowand/or (iii) decrease or inhibit sodium reabsorption in an individual inneed thereof are provided. The compounds may also find use in treating adisease or condition that is, or is expected to be, responsive to (i) areduction in an individual's blood pressure and/or (ii) an increase inrenal blood flow and/or (iii) a decrease or inhibition of sodiumreabsorption. The individual may be a human who has been diagnosed withor is suspected of having high blood pressure or a disease or conditionthat is, or is expected to be, responsive to (i) a reduction in anindividual's blood pressure and/or (ii) an increase in renal blood flowand/or (iii) a decrease or inhibition of sodium reabsorption. Theindividual may be a human who exhibits one or more symptoms associatedwith high blood pressure or a disease or condition that is, or isexpected to be, responsive to (i) a reduction in an individual's bloodpressure and/or (ii) an increase in renal blood flow and/or (iii) adecrease or inhibition of sodium reabsorption. The individual may be ahuman who is genetically or otherwise predisposed to developing highblood pressure or a disease or condition that is, or is expected to be,responsive to (i) a reduction in an individual's blood pressure and/or(ii) an increase in renal blood flow and/or (iii) a decrease orinhibition of sodium reabsorption. In one variation, the compounds mayfind use in treating metabolic syndrome. In some embodiments, thecompounds are adrenergic receptor α_(2B) antagonists. In one variation,the adrenergic receptor α_(2B) antagonists are selective adrenergicreceptor α_(2B) antagonists. In one variation, a compound that is anadrenergic receptor α_(2B) antagonist also showing adrenergic receptorα_(2A) antagonist and/or inverse agonist activity may find use reducingblood pressure in an individual with hypertension who is also sufferingfrom obesity, type-2 diabetes and/or metabolic syndrome. Thus, providedis a method for lowering blood pressure in hypertensive patients with adisease or condition that is responsive to treatment using an antagonistor inverse agonist of adrenergic receptor α_(2A), such as obesity and/ortype-2 diabetes and/or metabolic syndrome.

Compounds detailed herein may be used in a method of treating a diseaseor condition that is responsive to (i) a reduction in an individual'sblood pressure and/or (ii) an increase in renal blood flow and/or (iii)a decrease or inhibition of sodium reabsorption. For example, thecompounds may find use in treating hypertension, includingtreatment-resistant hypertension. In some embodiments, the compounds maybe used in a method of treating hypertension in an individual notsuffering from obesity or type-2 diabetes. In some embodiments, thecompounds are adrenergic receptor α_(2B) antagonists. In someembodiments, the compounds are selective adrenergic receptor α_(2B)antagonists.

In one aspect, the disease or indication is a cardiac or renal diseaseor indication for which (i) a reduction in an individual's bloodpressure and/or (ii) an increase in renal blood flow and/or (iii) adecrease or inhibition of sodium reabsorption would be, or would beexpected to be, beneficial. Such cardiac indications include, but arenot limited to, heart failure, such as compensated heart failure,decompensated heart failure, acute decompensated congestive heartfailure and chronic congestive heart failure, coronary heart disease,cardiac arrhythmias, myocardial ischemia, and hypertrophy. Such renalindications include, but are not limited to, renal failure such aschronic renal failure, acute renal failure and endstage renal failure,renal ischemia and chronic kidney disease. Other indications for which(i) a reduction in an individual's blood pressure and/or (ii) anincrease in renal blood flow and/or (iii) a decrease or inhibition ofsodium reabsorption would be, or would be expected to be, beneficialinclude but are not limited to sleep apnea and ischemic attacks.

Compounds detailed herein may also ameliorate symptoms of a disease orcondition that have a cardiac or renal component in which (i) areduction in an individual's blood pressure and/or (ii) an increase inrenal blood flow and/or (iii) a decrease or inhibition of sodiumreabsorption would be, or would be expected to be, beneficial. Forexample, the compounds may reduce elevated blood pressure, improveshortness of breath, reduce tachycardia, reduce edema, reduce elevatedblood urea nitrogen to creatinine (BUN/Cr) ratio, improve creatininelevels, improve the ability to lie flat, reduce the incidence orseverity of high blood pressure, reduce the risk and/or number of acutecardiac events (e.g., acute decompensation or myocardial infarction) anindividual experiences over a period of time (e.g., one year, 2 years, 5years, etc.), reduce the incidence of acute heart failure an individualexperiences over a period of time (e.g., one year, 2 years, 5 years,etc.), reduce the severity and/or incidence of pulmonary congestionand/or reduce the risk of stroke, reduce shortness of breath and/ortachycardia in individuals after myocardial infarction, improve leftventricular ejection fraction (LVEF) post infarct and/or lower weightand blood pressure in obese individuals (e.g., men and women) withpre-hypertension. In some embodiments, the compounds are adrenergicreceptor α_(2B) antagonists. In some embodiments, the compounds areselective adrenergic receptor α_(2B) antagonists.

Compounds detailed herein (such as the adrenergic receptor α_(2B)antagonists detailed herein) may find use in the treatment ofhypertensive emergencies. Provided is a method of treating hypertensiveemergencies, comprising administering intravenously an effective amountof an adrenergic receptor α_(2B) antagonist to an individual in needthereof. In some embodiments, the method comprises administeringintravenously an effective amount of an adrenergic receptor α_(2B)antagonist to an individual in need thereof in a highly monitoredintensive care setting, wherein the administration results in aggressiveand controlled blood pressure lowering in the individual. In someembodiments, intravenous administration of an adrenergic receptor α_(2B)antagonist in an individual results in gradually lowering of bloodpressure in the individual and minimizing damage of end organs such asthe brain, kidney, heart, and eye. Particularly useful in the treatmentof hypertensive emergencies or crisis are parenteral formulations of anadrenergic receptor α_(2B) antagonist detailed herein. In one variation,the compound is an adrenergic receptor α_(2B) antagonist. In somevariations, the compound is a selective adrenergic receptor α_(2B)antagonist. In one variation, the adrenergic receptor α_(2B) antagonistalso exhibits adrenergic receptor α_(2A) antagonist and/or inverseagonist activity.

In one variation, a method of decreasing the severity and/or incidenceof shortness of breath, tachycardia, edema, and/or the inability to lieflat is provided, comprising administering an effective amount of acompound detailed herein to an individual who has or is suspected ofhaving heart failure (e.g., compensated heart failure and decompensatedheart failure). In another variation, a method of decreasing theseverity and/or incidence of elevated BUN/Cr, and/or edema is providedcomprising administering an effective amount of a compound detailedherein to an individual who has or is suspected of having renal failure(e.g., acute or chronic renal failure). In another variation, a methodof reducing blood pressure in an individual is provided comprisingadministering an effective amount of a compound detailed herein to anindividual who has or is suspected of having hypertension (e.g.,treatment-resistant hypertension). In another variation, a method ofdecreasing the severity and/or incidence of shortness of breath,tachycardia, and/or improving LVEF post infarct in an individual isprovided comprising administering an effective amount of a compounddetailed herein to an individual who has experienced myocardialinfarction (e.g., an individual who has recently experienced myocardialinfarction such as within 30 minutes, 1, 3, 6, 12, or 24 hours oftreatment). In some of the variations, the adrenergic receptor α_(2B)antagonist is a selective adrenergic receptor α_(2B) antagonist. In someof the variations, the adrenergic receptor α_(2B) antagonist alsoexhibits antagonist activity for the adrenergic receptor α_(2A). In someembodiments, the compounds are adrenergic receptor α_(2B) antagonists.In some embodiments, the compounds are selective adrenergic receptorα_(2B) antagonists.

In one variation, provided is method for lowering the blood pressure inan individual in need thereof comprising administering to the individuala compound described herein, or a pharmaceutically acceptable saltthereof. Administration of an adrenergic receptor α_(2B) antagonistdetailed herein lowers the blood pressure in the individual from a levelconsidered above the desired level for such individual. The bloodpressure lowering therapy such as administration of compounds detailedherein is intended to help hypertensive individuals reach their bloodpressure goals defined by their individual cardiovascular risk factors.For example, for otherwise healthy individuals without diabetes or knowncardiovascular disease, goal blood pressure is less than about 140/90mmHg; for patients with known cardiovascular disease (e.g., priormyocardial infarction, peripheral vascular disease) goal blood pressureis less than about 130-135/85 mmHg; for patients with diabetes, goalblood pressure is less than about 130/80 mmHg.

In one variation, compounds provided herein may have any one or more ofthe following beneficial effects on an individual: (1) reduce arterialblood pressure (e.g., in an individual with hypertension, certain formsof heart failure and/or renal failure); (2) reduce pulse pressure (e.g.,in an individual with hypertension, certain forms of heart failureand/or renal failure); (3) tachycardia-preserved baroreceptor activity(e.g., in an individual whose systolic blood pressure is expected to ordoes fall in response to an α_(2B) antagonist), which may suggest a lackof orthostatic hypotension; and (4) bradycardia-reduced cardiac workload and added reduction on blood pressure reduction by further reducingcardiac output (e.g., in an individual who has been administered atherapy that is an α_(2B) and α_(1B) mixed antagonist).

In another variation, compounds provided herein may exert theirtherapeutic effect with no or reduced side-effects, such as whencompared to other therapies used in the treatment of the same or similarindication. In one aspect, compounds provided herein exhibit no orreduced side effects upon administration to an individual, wherein theside effects may be any one or more of: (i) reduced libido, (ii)orthostatic hypotension, (iii) muscle weakness, (iv) fatigue, (v)erectile dysfunction, (vi) constipation, (vii) depression, (viii)dizziness, (ix) dry mouth, (x) impaired thinking, (xi) weight gain,(xii) persistent cough, (xiii) chest pain, (xiv) headache, (xv) fluidretention, (xvi) racing pulse, and (xvii) emesis.

In one aspect, compounds are provided that do not bind appreciably anyone or more of the histamine, dopamine and serotonin receptors. In anyof the methods detailed herein, in one variation the individual does nothave a cognitive disorder, psychotic disorder, neurotransmitter-mediateddisorder and/or neuronal disorder. As used herein, the term “cognitivedisorders” refers to and intends diseases and conditions that arebelieved to involve or be associated with or do involve or areassociated with progressive loss of structure and/or function ofneurons, including death of neurons, and where a central feature of thedisorder may be the impairment of cognition (e.g., memory, attention,perception and/or thinking). These disorders include pathogen-inducedcognitive dysfunction, e.g., HIV associated cognitive dysfunction andLyme disease associated cognitive dysfunction. Examples of cognitivedisorders include Alzheimer's Disease, Huntington's Disease, Parkinson'sDisease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism,mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI)and age-associated memory impairment (AAMI). As used herein, the term“psychotic disorders” refers to and intends mental diseases orconditions that are believed to cause or do cause abnormal thinking andperceptions. Psychotic disorders are characterized by a loss of realitywhich may be accompanied by delusions, hallucinations (perceptions in aconscious and awake state in the absence of external stimuli which havequalities of real perception, in that they are vivid, substantial, andlocated in external objective space), personality changes and/ordisorganized thinking. Other common symptoms include unusual or bizarrebehavior, as well as difficulty with social interaction and impairmentin carrying out the activities of daily living. Exemplary psychoticdisorders are schizophrenia, bipolar disorders, psychosis, anxiety anddepression. As used herein, the term “neurotransmitter-mediateddisorders” refers to and intends diseases or conditions that arebelieved to involve or be associated with or do involve or areassociated with abnormal levels of neurotransmitters such as histamine,serotonin, dopamine, norepinephrine or impaired function of aminergic Gprotein-coupled receptors. Exemplary neurotransmitter-mediated disordersinclude spinal cord injury, diabetic neuropathy, allergic diseases anddiseases involving geroprotective activity such as age-associated hairloss (alopecia), age-associated weight loss and age-associated visiondisturbances (cataracts). Abnormal neurotransmitter levels areassociated with a wide variety of diseases and conditions including, butnot limited, to Alzheimer's disease, Parkinson's Disease, autism,Guillain-Barré syndrome, mild cognitive impairment, schizophrenia,anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cordinjury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis,depression and a variety of allergic diseases. As used herein, the term“neuronal disorders” refers to and intends diseases or conditions thatare believed to involve, or be associated with, or do involve or areassociated with neuronal cell death and/or impaired neuronal function ordecreased neuronal function. Exemplary neuronal indications includeneurodegenerative diseases and disorders such as Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson'sdisease, canine cognitive dysfunction syndrome (CCDS), Lewy bodydisease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahrdisease, an acute or chronic disorder involving cerebral circulation,such as ischemic or hemorrhagic stroke or other cerebral hemorrhagicinsult, age-associated memory impairment (AAMI), mild cognitiveimpairment (MCI), injury-related mild cognitive impairment (MCI),post-concussion syndrome, post-traumatic stress disorder, adjuvantchemotherapy, traumatic brain injury (TBI), neuronal death mediatedocular disorder, macular degeneration, age-related macular degeneration,autism, including autism spectrum disorder, Asperger syndrome, and Rettsyndrome, an avulsion injury, a spinal cord injury, myasthenia gravis,Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy,fibromyalgia, neuropathy associated with spinal cord injury,schizophrenia, bipolar disorder, psychosis, anxiety or depression.

Individuals who have high blood pressure, or a disease or condition thatis, or is expected to be, responsive to (i) a reduction in anindividual's blood pressure and/or (ii) an increase in renal blood flowand/or (iii) a decrease or inhibition of sodium reabsorption may benefitfrom the compounds detailed herein, including the adrenergic receptorα_(2B) antagonists (e.g., the selective adrenergic receptor α_(2B)antagonist) detailed herein.

An individual who does not have high blood pressure or a disease orcondition that is, or is expected to be, responsive to (i) a reductionin an individual's blood pressure and/or (ii) an increase in renal bloodflow and/or (iii) a decrease or inhibition of sodium reabsorption maynevertheless benefit from the compounds detailed herein if theindividual has one or more risk factors for high blood pressure, or adisease or condition that is, or is expected to be, responsive to (i) areduction in an individual's blood pressure and/or (ii) an increase inrenal blood flow and/or (iii) a decrease or inhibition of sodiumreabsorption. Risk factors for developing high blood pressure mayinclude gender, race, ethnicity, age, family history, weight and/orlifestyle. For example, African-Americans, men (particularly if over age45), woman over age 55, anyone over age 60, pre-hypertension individuals(individuals with a blood pressure of 120-130/80-89 mmHg), individualswho are overweight or obese, individuals with sleep apnea (such asobstructive sleep apnea), individuals who smoke, individuals who have ahigh salt diet, individuals who have a low potassium diet, individualswith chronic heavy alcohol use, individuals with a sedentary lifestyle,individuals with moderate to high stress, individuals with compromisedrenal function or renal failure and individuals with close relatives whohave high blood pressure are each at an increased risk of developinghigh blood pressure themselves, or diseases or conditions associatedwith high blood pressure. Individuals with more than one such riskfactor are particularly susceptible to developing high blood pressure.Risk factors for developing kidney disease may include diabetes, highblood pressure (hypertension), cardiovascular diseases, smoking,obesity, high cholesterol, a family history of kidney disease, and/orage 65 or older. Members of certain ethnic groups are also at higherrisk for kidney disease including people of Aboriginal, Asian, southAsian, Pacific Island, African/Caribbean, American Indian and Hispanicorigin.

Cell Viability and Mitochondrial Health

Methods of promoting cellular viability by promoting mitochondrialhealth are provided, the methods comprising contacting the cell with acompound detailed herein. The methods are applicable to various cells,such as neuronal and non-neuronal cells. In one variation, the cell is anon-neuronal cell, such as a renal or cardiac cell (e.g., myocardialmuscle cell). In one aspect, methods of promoting cellular viability areprovided wherein the cell is one whose viability would be, or would beexpected to be, promoted by nutrient influx and/or oxygenation. Methodsof promoting cellular viability in a cell experiencing, or exhibitingsymptoms of, mitochondrial stress are also provided.

Methods of treating a disease or condition that is, or is expected tobe, responsive to promoting mitochondrial health and cell viability arealso described, the methods comprising administering to an individual inneed thereof an effective amount of a compound provided herein. In onevariation, the disease or condition is one which is associated withdysfunction of mitochondria in a non-neuronal cell. In a particularvariation, the disease or condition is one which is associated withdysfunction of mitochondria in a renal or cardiac cell (e.g., myocardialmuscle cell). In another variation, the disease or condition is onewhich would benefit from cellular (e.g., renal or cardiac) nutrientinflux and/or oxygenation.

Thus, individuals who have a disease or condition that is associatedwith, or believed to be associated with, mitochondrial dysfunction maybenefit from the compounds detailed herein, or pharmaceuticallyacceptable salts thereof. An individual who has a disease or conditionthat is associated with mitochondrial dysfunction should experience oneor more beneficial or desirable results upon administration of aneffective amount of a compound provided herein, or pharmaceuticallyacceptable salt thereof. In one aspect, the beneficial or desirableresult is an increase in nutrient influx and/or oxygenation of a cell.In another aspect, the beneficial or desirable result is a reduction inthe number and/or severity of symptoms associated with a disease orcondition that is associated with mitochondrial dysfunction.

In one variation, a method of treating a renal or cardiac condition isprovided, comprising administering to an individual in need thereof acompound as detailed herein. Such conditions include, but are notlimited to, renal failure, such as acute renal failure and chronic renalfailure, coronary (e.g., myocardial) ischemia, heart failure, such asacute and chronic congestive heart failure (including the muscle fatigueassociated with these conditions), and coronary artery disease. Methodsof treating other diseases and conditions are also described, such asmethods of treating sleep apnea, acute respiratory distress syndrome(adult and infant) and peripheral vascular disease. The compounds asprovided herein may also be used in a method of delaying the onsetand/or development of a disease or condition associated withmitochondrial dysfunction, comprising administering a compound asprovided herein, or a pharmaceutical salt thereof, to an individual whois at risk of developing a disease or condition associated withmitochondrial dysfunction.

Compounds that do not bind appreciably to neurotransmitter receptors butnevertheless enhance mitochondrial function, e.g., when administered tocells in the setting of mitochondrial stress (e.g., excess intracellularcalcium), may be used in the methods herein to promote cell survival. Inone aspect, the compounds exhibit the ability to enhance mitochondrialfunction by protecting against cell death mediated by mitochondrialdysfunction in an assay detailed herein. Thus, it is understood andclearly conveyed that enhancing mitochondrial function includesprotecting a cell against cell death mediated by mitochondrialdysfunction. The compounds may also be assessed in assays known in theart.

It is understood and clearly conveyed that the binding and activityprofiles detailed herein (e.g., in the disclosure above) in onevariation apply to the formulae provided herein (e.g., the formulae foruse in the methods). In one aspect, selective adrenergic receptor α_(2B)antagonists are of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3),(B4), (C1), (C2), (C3), (C4), (D1), (D2), (D3), -(D4), and variationsthereof.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and elsewhere. The invention includesthe use of all of the compounds described herein, including any and allstereoisomers, including geometric isomers (cis/trans or E/Z isomers),salts and solvates of the compounds described herein, as well as methodsof making such compounds.

In one aspect, compounds of formulae (A1)-(A2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(4a) are taken together to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(2a) and R^(2b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(2a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a)and R^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken togetherto form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o and p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h),where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol,—S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,—S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstitutedamino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In some variations, compounds of the formula (A1), and salts andsolvates thereof, are embraced, provided that:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, acyloxy, cyano,alkynyl, acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b), oramino substituted with one or two substituted or unsubstituted C₁-C₈alkyl; and

(2) when each m, n, o and p is 0 and R⁵ is methyl, then Q is substitutedor unsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, alkynyl, aminocarbonylalkoxy, a group of the formula—CR⁹═CR^(10a)R^(10b), or amino substituted with one or two substitutedor unsubstituted C₁-C₈ alkyl;

(3) wherein at least one of m, n, o and p is 1 and R⁵ is H, then Qsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy,carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); and

(4) wherein at least one of m, n, o and p is 1 and R⁵ is methyl, then Qsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl other than a substituted piperazinyl, aminoacyl, acyloxy,carboxyl, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a groupof the formula —CR⁹═CR^(10a)R^(10b), or amino substituted with one ortwo substituted or unsubstituted C₁-C₈ alkyl.

In one variation, compounds of the formula (A1), and salts and solvatesthereof, are embraced, provided that when none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring, atleast one of m, n, o and p is 1 and each R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, alkoxy,acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted orunsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(8(a-h))to form a substituted or unsubstituted methylene moiety or is takentogether with a geminal R^(8(a-h)) and the carbon to which they areattached to form a carbonyl moiety, then:

(i) when Q is a carbonylalkoxy of the formula —COOCH₃ and R⁵ is anunsubstituted C₁-C₈ alkyl where the unsubstituted C₁-C₈ alkyl is methyl,then one or more of provisions (a)-(d) apply: (a) at least one of X¹, X²and X³ is N or CR⁶; (b) R^(2a) and R^(2b) are both H; (c) R¹ is H or anunsubstituted C₁-C₈ alkyl; and (d) R⁵ is H;(ii) when either (1) Q is carbonylalkoxy of the formula —COOCH₃ or—COOCH₂CH₃ or (2) Q is an alkoxy of formula —OCH₃ or —OCH₂CH₃ and isbound to a carbonyl group to form a moiety of the formula —COOCH₃ or—COOCH₂CH₃, then one or more of provisions (a)-(c) apply: (a) at leastone of X¹, X² and X³ is N or CR⁶, provided that if X² is CR⁶ where R⁶ ismethyl, then R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R⁵ is anunsubstituted C₁-C₈ alkyl; and (c) at least one of n, m, o and p is 1;(iii) when either (1) Q is an acylamino of the formula —CONH₂ or (2) Qis an unsubstituted amino bound to a carbonyl group to form a moiety ofthe formula —CONH₂, then one or more of provisions (a)-(e) apply: (a) atleast one of X¹, X² and X³ is N or CR⁶, provided that if X² is CR⁶ whereR⁶ is methyl, then R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R⁵ is anunsubstituted C₂-C₈ alkyl; (c) R⁵ and R¹ are independently anunsubstituted C₁-C₈ alkyl; (d) at least one of n, m, o and p is 1; and(e) when R⁵ is an unsubstituted C₁-C₈ alkyl, then R^(2a) and R^(2b) areboth H;(iv) when Q is cyano, then one or more of provisions (a)-(d) apply: (a)at least one of X¹, X² and X³ is N or CR⁶; (b) R^(2a) and R^(2b) areboth H; (c) R¹ is an unsubstituted C₁-C₈ alkyl; and (d) at least one ofn, m, o and p is 1;(v) when Q is an acyloxy of the formula —COOH, then one or more ofprovisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶;(b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) at least one of n, m, oand p is 1;(vi) when Q is an acyloxy of the formula —COO-substituted alkyl, thenone or more of provisions (a)-(c) apply: (a) at least one of X¹, X² andX³ is N or CR⁶; (b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) R¹ isother than H.

In some variations, compounds of the formula (A2), and salts andsolvates thereof, are embraced, provided that:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, cyano, alkynyl, aminocarbonylalkoxy,acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b), or aminosubstituted with one or two substituted or unsubstituted C₁-C₈ alkyl;

(2) when each m, n, o and p is 0 and R⁵ is unsubstituted C₁-C₈ alkyl,then Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino,aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); and

(3) when at least one of m, n, o and p is 1 and R⁵ is H, then Q issubstituted or unsubstituted aryl other than unsubstituted phenyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted amino, aminoacyl,acyloxy, cyano, alkynyl, aminocarbonylalkoxy, or is a group of theformula —CR⁹═CR^(10a)R^(10b).

In one variation, compounds of the formula (A2), and salts and solvatesthereof, are embraced, provided that:

(i) when m, n, o and p are each 0 and Q is a substituted aryl whereinthe substituted aryl is a carboline moiety, then one or more ofprovisions (a)-(c) apply: (a) X¹, X² and X³ are independently N or CH;(b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) R¹ is an unsubstitutedC₁-C₈ alkyl;(ii) when none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b)are taken together to form a ring, at least one of m, n, o and p is 1and each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) andR^(8h) is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl,—S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,—S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstitutedamino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety, then:

(A) when Q is a carboxyl moiety, then one or more of provisions (a)-(e)apply: (a) at least one of X¹, X² and X³ is independently N or CR⁶; (b)two or more of m, n, o and p are 1; (c) at least one of R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) is other than H; (d)when R⁵ is an unsubstituted C₁-C₈ alkyl then at least one of m, n, o andp is 1; and (e) when R⁵ is H then R^(2a) and R^(2b) are each H;

(B) when one of R^(2a) and R^(2b) is methyl or when R^(2a) and R^(2b)are taken together to form a carbonyl, then one or more of provisions(a)-(c) apply: (a) R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R¹ is anunsubstituted C₁-C₈ alkyl; and (c) Q is a substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, aminoacyl, cyano,alkynyl, aminocarbonylalkoxy; and

(C) when R¹ and R^(2a) are taken together to form a butylene(—CH₂CH₂CH₂CH₂—), then one or more of provisions (a)-(d) apply: (a) R⁵is an unsubstituted C₁-C₈ alkyl; (b) the 6-membered ring formed when R¹and R^(2a) are taken together to form a butylene (—CH₂CH₂CH₂CH₂—) moietyis not further substituted with a cyclic structure and is notsubstituted with an alkenyl or cyano-containing moiety; (c) X³ is CH andX¹ and X² are independently N or CR⁶; and (d) Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl,aminocarbonylalkoxy or acylamino moiety.

In specific variations, compounds of formula (A1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, X¹, X², X³,R^(8(a-h)), m, n, o, p and Q, where present, are defined as for formula(A1) and, where applicable, any variation thereof detailed herein. Thatis, variations of formula (A1) detailed throughout, where applicable,apply equally to any of formulae (A1a)-(A1c) the same as if each andevery variation were specifically and individually listed for formulae(A1a)-(A1c). Pharmaceutically acceptable salts of compounds of formulae(A1a)-(A1c) are also provided.

In specific variations, compounds of formula (A1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³, R^(8(a-h)) andQ, where present, are defined herein and, where applicable, anyvariation thereof detailed herein. That is, variations of the formula(A1) detailed throughout, where applicable, apply equally to any offormulae (A1d)-(A1h) the same as if each and every variation werespecifically and individually listed for formulae (A1d)-(A1h).Pharmaceutically acceptable salts of compounds of formulae (A1d)-(A1h)are also provided.

In another variation, compounds of formula (A1) have the structure:

or a salt or solvate thereof; wherein R⁵, R^(8(a-h)), X¹, X², X³ and Q,where present, are defined herein and, where applicable, any variationthereof detailed herein. That is, variations of the formula (A1)detailed throughout, where applicable, apply equally to any of formulae(A1i)-(A1r) the same as if each and every variation were specificallyand individually listed for formulae (A1i)-(A1r). In one embodiment,compounds of the formula (A1) are provided wherein the compounds are ofthe formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) beingtaken together with R^(2a) of formula (A1) to provide compounds of theformula (A1i)-(A1r), R¹ is taken together with R^(3a) to form apropylene moiety or a butylene moiety. In another embodiment, compoundsof the formula (A1) are provided wherein the compounds are of theformula (A1i)-(A1r) except that, instead of R¹ of formula (A1) beingtaken together with R^(2a) of formula (A1) to provide compounds of theformula (A1i)-(A1r), R¹ is taken together with R^(4a) to form anethylene moiety or a propylene moiety. In a further embodiment,compounds of the formula (A1) are provided wherein the compounds are ofthe formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) beingtaken together with R^(2a) of formula (A1) to provide compounds of theformula (A1i)-(A1r), R^(2a) and R^(3a) are taken together to form anethylene moiety or a propylene moiety. In still a further embodiment,compounds of the formula (A1) are provided wherein the compounds are ofthe formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) beingtaken together with R^(2a) of formula (A1) to provide compounds of theformula (A1i)-(A1r), R^(2a) and R^(4a) are taken together to form amethylene moiety or an ethylene moiety. In yet another embodiment,compounds of the formula (A1) are provided wherein the compounds are ofthe formula (A1i)-(A1r) except that, instead of R¹ of formula (A1) beingtaken together with R^(2a) of formula (A1) to provide compounds of theformula (B1)-(B10), R^(3a) and R^(4a) are taken together to form apropylene moiety or a butylene moiety. Variations detailed throughout,where applicable, apply to such formulae the same as if each and everyvariation were specifically and individually listed. Pharmaceuticallyacceptable salts of such formulae are also provided. Pharmaceuticallyacceptable salts of compounds of formulae (A1i)-(A1r) are also provided.

All variations referring to the formulae herein, such as formulae(A1a)-(A1r), where applicable, may apply to formula (A2), the same as ifeach and every variation were specifically and individually listed.

In some embodiments, compounds of the formula (A1a) have the structures(F1)-(F5):

wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^(8c), where present, is H, OH or substituted or unsubstituted C₁-C₈alkyl;

R^(8d), where present, is H or substituted or unsubstituted C₁-C₈ alkyl,and the bond indicates the presence of either an E or Z double bondconfiguration;

Y, where present, is O or NR¹¹;

each R¹¹, R^(12a) and R^(12b) is independently H or substituted orunsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

provided that when the compound is of the formula (F5), D is other thanunsubstituted phenyl.

In some embodiments, the compound is of the formula (F1). In someembodiments, wherein the compound is of the formula (F2). In someembodiments, the compound is of the formula (F3). In some embodiments,the compound is of the formula (F4). In some embodiments, the compoundis of the formula (F5).

In another aspect, compounds of formulae (A3)-(A4) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a), R^(2b) R^(3a), R^(3b), R^(4a), R^(4b), R^(10a) and R^(10b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R², R³,R⁴ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h),where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol,—S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,—S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstitutedamino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In a particular variation, compounds of formula (A3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶ and R^(8(a-h)), wherepresent, and Q are defined as for formula (A3) and, where applicable,any variation thereof detailed herein. That is, variations of formula(A3) detailed throughout, where applicable, apply to formulae(A3a)-(A3e) the same as if each and every variation were specificallyand individually listed for formulae (A3a)-(A3e). Pharmaceuticallyacceptable salts of compounds of formulae (A3a)-(A3e) are also provided.

In particular variation, compounds of formula (A3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X² and X³ are definedas for formula (A3) and, where applicable, any variation thereofdetailed herein, n is 0-5, o is 0-4, p is 0-3, Z is NH, N—CH₃, O or S,and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted aryloxy, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino. In one particularaspect of this variation, W is H, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In one particular aspect ofthis variation, Z is S. In another particular aspect of this variation,one of X¹, X² or X³ is N. Variations of formula (A3) detailedthroughout, where applicable, apply equally to any of formulae(A3f)-(A3h), the same as if each and every variation were specificallyand individually listed for formula (A3f)-(A3h). Pharmaceuticallyacceptable salts of compounds of formulae (A3f)-(A3h) are also provided.

All variations referring to the formulae herein, such as formulae(A3a)-(A3h), where applicable, may apply to formula (A4), the same as ifeach and every variation were specifically and individually listed.

In another aspect, compounds of formulae (B1)-(B2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(4a) are taken together to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(2a) and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(4a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R^(2a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(5a) and R^(5b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or

when m-o are each 0, then R^(5a) and R^(7a) are taken together to form abond, or

when m is 1, and n-o are each 0, then R^(5a) and R^(7c) are takentogether to form a bond, or

when m-n are each 1, and o is 0, then R^(5a) and R^(7e) are takentogether to form a bond, or

when m-o are each 1, then R^(5a) and R^(7g) are taken together to form abond;

each m, n and o is independently 0 or 1;

each X¹, X² and X³ is independently N, CH or CR⁶;

Y¹ is CR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ isNR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d);

Y², where present, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, providedthat when Y² is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³,where present, is CR^(7e)R^(7f);

Y³, where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, providedthat when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h);

Y⁴, where present, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, providedthat when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f);

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(7a) and R^(7b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7a) and R^(7b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7a) and R^(7c), where present,are taken together to form a bond;

each R^(7c) and R^(7d), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;

each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;

each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or

R^(7g) and R^(7e) are taken together to form a bond, or R^(7g) andR^(5a) are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In one variation, compounds of the formula (B1) where m-o are each 0,and salts and solvates thereof, are embraced, provided that when Y¹ isCR^(7a)R^(7b) where R^(7a) and R^(7b) are both H and none of R¹, R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form aring, then (i) at least one of R^(5a) and R^(5b) is other than H, and(ii) when at least one of R^(5a) and R^(5b) is other than H, then one ormore of provisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is Nor CR⁶; (b) R^(5a) and R^(5b) are both other than H; and (c) R^(5a) is Hand R^(5b) is an unsubstituted aryl other than phenyl.

In another variation, compounds of the formula (B1) where m-o are each0, and salts and solvates thereof, are embraced, provided that when Y¹is CR^(7a)R^(7b) where R^(7a) and R^(7b) are both H and none of R¹,R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are taken together toform a ring, then (i) when each R^(5a) and R^(5b) is H, at least one ofX¹, X² and X³ is N or CR⁶ where R⁶ is other than unsubstituted andsubstituted phenyl; and (ii) when at least one of R^(5a) and R^(5b) isother than H, then one or more of provisions (a)-(c) apply: (a) at leastone of X¹, X² and X³ is N or CR⁶; (b) R^(5a) and R^(5b) are both otherthan H; and (c) R^(5a) is H and R^(5b) is an unsubstituted aryl otherthan phenyl.

In one variation, compounds of the formula (B2) where m-o are each 0,and salts and solvates thereof, are embraced, provided that when Y¹ isCR^(7a)R^(7b) where R^(7a) and R^(7b) are both H and none of R¹, R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form aring, then at least one of R^(5a) and R^(5b) is other than H.

In one variation, compounds of the formula (B1) where m is 1 and n-o areeach 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are each H and Y¹is O or CR^(7a)R^(7b) where R^(7a) and R^(7b) are each H and none of R¹,R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are taken together toform a ring, then (i) at least one of R^(5a) and R^(5b) is other than H,and (ii) when at least one of R^(5a) and R^(5b) is other than H, thenone or more of provisions (a)-(c) apply: (a) at least one of X¹, X² andX³ is N or CR⁶; (b) R^(5a) and R^(5b) are each other than H; and (c) atleast one of R^(5a) and R^(5b) is a substituted or unsubstitutedheteroaryl, a substituted aryl or an unsubstituted aryl other thanphenyl;

(2) when Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are each H and Y¹is S and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b)are taken together to form a ring, then (i) at least one of R^(5a) andR^(5b) is other than H, and (ii) when at least one of R^(5a) and R^(5b)is other than H, then one or more of provisions (a)-(c) apply: (a) atleast one of X¹, X² and X³ is N or CR⁶; (b) R^(5a) and R^(5b) are eachother than H; and (c) at least one of R^(5a) and R^(5b) is a substitutedor unsubstituted heteroaryl or aryl moiety;

(3) when Y¹ is NH, none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a)and R^(4b) are taken together to form a ring, and R^(7c), if present, isnot taken together with R^(5a) to form a bond, then one or more ofprovisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶;(b) Y² is other than C(O); and (c) at least one of R^(5a) and R^(5b) isother than H; and

(4) when Y¹ is NR⁸ where R⁸ is methyl, none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring, andR^(7c), if present, is not taken together with R^(5a) to form a bond,then one or both of provisions (a) and (b) apply: (a) at least one ofX¹, X² and X³ is N or CR⁶ and (b) at least one of R^(5a) and R^(5b) isother than H and methyl.

In another variation, compounds of the formula (B1) where m is 1 and n-oare each 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^(7a)R^(7b) where R^(7a) and R^(7b) are each H, Y² isCR^(7c)R^(7d) where R^(7c) and R^(7d) are each H, and none of R¹,R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are taken together toform a ring, then one or more of provisions (i)-(iii) apply: (i) atleast one of R^(5a) and R^(5b) is other than H and at least one of X¹,X² and X³ is N or CR⁶; (ii) when each of R^(5a) and R^(5b) is H, atleast one of X¹, X² and X³ is N or CR⁶ where R⁶ is chloro or substitutedor unsubstituted alkyl (e.g., methyl); and (iii) when each of X¹, X² andX³ is CH, at least one of R^(5a) and R^(5b) is other than H, phenyl andCH₂CH₂NMe₂;

(2) when Y¹ is O or S and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b),R^(4a) and R^(4b) are taken together to form a ring, then (i) when Y² isCR^(7c)R^(7d) where R^(7c) and R^(7d) are each H, at least one of R^(5a)and R^(5b) is other than H; or (ii) when Y² is CR^(7c)R^(7d) where oneof R^(7c) and R^(7d) is H and the other is phenyl, at least one ofR^(5a) and R^(5b) is other than H or at least one of X¹, X² and X³ is Nor CR⁶;

(3) when Y¹ is NR⁸ where R⁸ is H, none of R¹, R^(2a), R^(2b), R^(3a),R^(3b), R^(4a) and R^(4b) are taken together to form a ring, and R^(7c)is not taken together with R^(5a) to form a bond, then one or both ofprovisions (i) and (ii) apply: (i) at least one of X¹, X² and X³ is N orCR⁶; and (ii) Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are not takentogether with the carbon to which they are attached to form a carbonylmoiety;

(4) when Y¹ is NR⁸ where R⁸ is methyl, none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring, andR^(7c) is not taken together with R^(5a) to form a bond, then at leastone of X¹, X² and X³ is N or CR⁶; and

(5) when Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are taken togetherwith the carbon to which they are attached to form a carbonyl moiety,none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are takentogether to form a ring, and each of X¹, X² and X³ is CH, then Y¹ is notNR⁸ where R⁸ is an alkyl substituted with a substituted amino group(e.g., (CH₂)₃NMe₂).

In one variation, compounds of the formula (B2) where m is 1 and n-o areeach 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^(7a)R^(7b) and Y² is CR^(7c)R^(7d) where each ofR^(7a), R^(7b), R^(7c) and R^(7d) is H, R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety, and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) andR^(4b) are taken together to form a ring, then one or more of provisions(a)-(d) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; (b) R^(5a)is H and R^(5b) is other than H; (c) at least one of R^(5a) and R^(5b)is a unsubstituted or unsubstituted heteroaryl or aryl moiety; and (d)R¹ is a substituted or unsubstituted C₁-C₈ alkyl;

(2) when Y¹ is NH, Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are eachH, none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) aretaken together to form a ring, and R^(7c), if present, is not takentogether with R^(5a) to form a bond, then (i) at least one of R^(5a) andR^(5b) is other than H, and (ii) when at least one of R^(5a) and R^(5b)is other than H, then one or both of provisions (a) and (b) apply: (a)at least one of R^(5a) and R^(5b) is other than an unsubstitutedC₁-C₈alkyl; (b) R¹ is a substituted or unsubstituted C₁-C₈ alkyl and atleast one of X¹, X² and X³ is N or CR⁶; and

(3) when Y¹ is O, Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are eachH, none of R, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) aretaken together to form a ring, and R^(7c), if present, is not takentogether with R^(5a) to form a bond, then one or more of provisions(a)-(d) apply: (a) when R^(5a) is H then R^(5b) is other than anunsubstituted C₁-C₈alkyl; (b) only one or more than two of X¹, X² and X³is CR⁶; (c) R¹ is other than H; and (d) at least one of R^(2a) andR^(2b) is H.

In another variation, compounds of the formula (B2) where m is 1 and n-oare each 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^(7a)R^(7b) and Y² is CR^(7c)R^(7d) where each ofR^(7a), R^(7b), R^(7c) and R^(7d) is H, and none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ringexcept that R^(2a) and R^(2b) may be taken together with the carbon towhich they are attached to form a cycloalkyl moiety, then (i) at leastone of R^(5a) and R^(5b) is other than H, and (ii) when one of R^(5a)and R^(5b) is an unsubstituted C₁-C₈alkyl, at least one of X¹, X² and X³is N or CR⁶;

(2) when Y¹ is CR^(7a)R^(7b) where both of R^(7a) and R^(7b) areunsubstituted C₁-C₈alkyl, Y² is CR^(7c)R^(7d) where each R^(7c) andR^(7d) is H, and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) andR^(4b) are taken together to form a ring, then (i) at least one ofR^(5a) and R^(5b) is other than H, or (ii) R¹ is a other than H; and

(3) when Y¹ is O, Y² is CR^(7c)R^(7d) where R^(7c) and R^(7d) are eachH, and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) aretaken together to form a ring, then one or more of provisions (a)-(d)apply: (a) when R^(5a) is H then R^(5b) is other than an unsubstitutedC₁-C₈alkyl; (b) only one or more than two of X¹, X² and X³ is CR⁶; (c)R¹ is other than H; and (d) at least one of R^(2a) and R^(2b) is H.

In one variation, compounds of the formula (B1) where m-n are each 1 ando is 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d) and Y³ isCR^(7e)R^(7f) where each of R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) andR^(7f) are H and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) andR^(4b) are taken together to form a ring, then one or both of provisions(a) and (b) apply: (a) at least one of R^(5a) and R^(5b) is other thanH; and (b) R¹ is an unsubstituted C₁-C₈ alkyl;

(2) when Y¹ is S or CR^(7a)R^(7b), Y² is S, S(O) or CR^(7c)R^(7d) and Y³is CR^(7e)R^(7f) where each of R^(7a), R^(7b), R^(7c), R^(7d), R^(7e)and R^(7f), if present, is H and none of R¹, R^(2a), R^(2b), R^(3a),R^(3b), R^(4a) and R^(4b) are taken together to form a ring and whereeither Y¹ is S and Y² is CR^(7c)R^(7d) or Y² is S or S(O) and Y¹ isCR^(7a)R^(7b), then (i) at least one of R^(5a) and R^(5b) is other thanH, and (ii) when at least one of R^(5a) and R^(5b) is other than H, thenone or both of provisions (a) and (b) apply: (a) at least one of X¹, X²and X³ is N or CR⁶; and (b) R¹ is methyl and at least one of R^(5a) andR^(5b) is a substituted or unsubstituted heteroaryl or aryl moiety;

(3) when Y¹ is O or CR^(7a)R^(7b), Y² is O or CR^(7c)R^(7d) and Y³ isCR^(7e)R^(7f) where each of R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) andR^(7f), if present, is H and none of R¹, R^(2a), R^(2b), R^(3a), R^(3b),R^(4a) and R^(4b) are taken together to form a ring and where either Y¹is O and Y² is CR^(7c)R^(7d) or Y² is O and Y¹ is CR^(7a)R^(7b), then(i) at least one of R^(5a) and R^(5b) is other than H, and (ii) when atleast one of R^(5a) and R^(5b) is other than H, then one or both ofprovisions (a) and (b) apply: (a) at least one of X¹, X² and X³ is N orCR⁶; and (b) R¹ is other than H; and

(4) when Y¹ is NH and Y³ is CR^(7e)R^(7f), where R^(7e) and R^(7f) areboth H, and where none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) andR^(4b) are taken together to form a ring then (i) at least one of R^(5a)and R^(5b) is other than H and (ii) when Y² is CR^(7c)R^(7d), R^(7c) andR^(7d) are not taken together to form a carbonyl moiety.

In another variation, compounds of the formula (B1) where m-n are each 1and o is 0, and salts and solvates thereof, are embraced, provided thatwhen R^(5a) and R^(5b) is H and none of R¹, R^(2a), R^(2b), R^(3a),R^(3b), R^(4a) and R^(4b) are taken together to form a ring, then one ormore of provisions (1) to (5) apply:

(1) when Y³ is CR^(7e)R^(7f) where one of R^(7e) and R^(7f) is anunsubstituted C₁-C₈alkyl, then one or more of provisions (i) to (iv)apply: (i) at least one of X¹, X² and X³ is N or CR⁶; (ii) Y² is otherthan CR^(7c)R^(7d) where each of R^(7c) and R^(7d) is H; (iii) Y¹ isother than S; and (iv) R¹ is other than H;

(2) when Y² is CR^(7c)R^(7d) and Y³ is CR^(7e)R^(7f) where each ofR^(7c), R^(7d), R^(7e) and R^(7f) is H, then (i) Y¹ is other thanCR^(7a)R^(7b) where each of R^(7a) and R^(7b) is H and NR⁸ where R⁸ isH; and (ii) when Y¹ is O, S or S(O), X² is N or CR⁶;

(3) when Y³ is CR^(7e)R^(7f) where each of R^(7e) and R^(7f) is H and Y²is CR^(7c)R^(7d) where at least one of R^(7c) and R^(7d) is other thanH, then one or both provisions (i) and (ii) apply: (i) at least one ofX¹, X² and X³ is N or CR⁶; and (ii) Y¹ is other than S and NH;

(4) when Y² is S and Y³ is CR^(7e)R^(7f) where each R^(7e) and R^(7f) isH, then one or more of provisions (i) to (iii) apply: (i) at least oneof X¹, X² and X³ is N or CR⁶; (ii) Y¹ is CR^(7a)R^(7b) where at leastone of R^(7a) and R^(7b) is other than H; and (iii) R¹ is other than H;and

(5) when Y² is O and Y³ is CR^(7e)R^(7f) where each R^(7e) and R^(7f) isH, then (i) Y¹ is CR^(7a)R^(7b) where at least one of R^(7a) and R^(7b)is other than H; and (ii) when Y¹ is CR^(7a)R^(7b) where one of R^(7a)and R^(7b) is methyl or phenyl, then one or both of provisions (a) and(b) apply: (a) at least one of X¹, X² and X³ is N or CR⁶; and (b) R¹ isother than H.

In one variation, compounds of the formula (B2) where m-n are each 1 ando is 0, and salts and solvates thereof, are embraced, provided that:

(1) when Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d) and Y³ isCR^(7e)R^(7f) where each of R^(7a), R^(7b), R^(7e) and R^(7f) are H andnone of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are takentogether to form a ring, then (i) when R^(7c) and R^(7d) are both H, atleast one of R^(5a) and R^(5b) is other than H, and (ii) when R^(7c) andR^(7d) are both methyl, then one or both of provisions (a) and (b)apply: (a) R^(2a) and R^(2b) are both H and (b) at least one of X¹, X²and X³ is N or CR⁶;

(2) when Y¹ is S or O, Y² is CR^(7c)R^(7d) and Y³ is CR^(7e)R^(7f) whereeach of R^(7c), R^(7d), R^(7e) and R^(7f) is H, and none of R¹, R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form aring, then one or both of provisions (a) and (b) apply: (a) at least oneof X¹, X² and X³ is N or CR⁶; and (b) at least one of R^(5a) and R^(5b)is other than H.

In one variation, compounds of the formula (B1) where m-o are each 1,and salts and solvates thereof, are embraced, provided that:

when Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d), Y³ is CR^(7e)R^(7f) andY⁴ is CR^(7g)R^(7h) where each of R^(7a), R^(7b), R^(7c), R^(7d),R^(7e), R^(7f), R^(7g) and R^(7h) are H, and none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring,then one or more of provisions (a)-(c) apply: (a) at least one of R^(5a)and R^(5b) is other than H; (b) at least one of X¹, X² and X³ is N orCR⁶; and (c) R¹ is other than H.

In another variation, compounds of the formula (B1) where m-o are each1, and salts and solvates thereof, are embraced, provided that when Y¹is CR^(7a)R^(7b) where each R^(7a) and R^(7b) is H, Y² is S, Y³ isCR^(7e)R^(7f) where each R^(7e) and R^(7f) is H, Y⁴ is CR^(7g)R^(7h)where each R^(7g) and R^(7h) is H, and none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring,then one or more of provisions (i)-(iii) apply: (i) at least one ofR^(5a) and R^(5b) is other than H; (ii) at least one of X¹, X² and X³ isN or CR⁶; and (iii) R¹ is other than H.

In one variation, compounds of the formula (B2) where m-o are each 1,and salts and solvates thereof, are embraced, provided that:

when Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d), Y³ is CR^(7e)R^(7f) andY⁴ is CR^(7g)R^(7h) where each of R^(7a), R^(7b), R^(7c), R^(7d),R^(7e), R^(7f), R^(7g) and R^(7h) are H, and none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring,then one or more of provisions (a)-(c) apply: (a) at least one of R^(5a)and R^(5b) is other than H; (b) at least one of X¹, X² and X³ is N orCR⁶; and (c) R¹ is other than H.

In specific variations, compounds of the formula (B1) have thestructure:

or a salt or solvate thereof; wherein R¹, R^(2a), R^(2b), R^(3a),R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R^(7(a-h)), X¹, X², X³, Y¹,Y², Y³ and Y⁴, where present, are defined as for formula (B1) and, whereapplicable, any variation thereof detailed herein. That is, variationsof formula (BI) detailed throughout, where applicable, apply to formulae(B1a)-(B1bm), the same as if each and every variation were specificallyand individually listed for formulae (B1a)-(B1bm). Pharmaceuticallyacceptable salts of compounds of formulae (B1a)-(B1bm) are alsoprovided.

In some variations, compounds of formula (B1) where m is 1 and n-o areeach 0 have the structure (B1bl), provided that:

(1) when Y¹ is CR^(7a)R^(7b) where each R^(7a) and R^(7b) is H, then oneor both of provisions (i) and (ii) apply: (i) R⁶ is other than H,fluoro, methoxy, unsubstituted phenyl and substituted phenyl; and (ii)at least one of R^(7c) and R^(7d) is other than H; and

(2) when Y¹ is NR⁸, O, S, S(O) or SO₂, then (iii) R^(7c) and R^(7d) arenot taken together with the carbon to which they are attached to form acarbonyl; and (iv) at least one of R^(7c) and R^(7d) is other than H,methyl and unsubstituted phenyl.

In some variations, compounds of formula (B1) where m is 1 and n-o areeach 0 have the structure (B1bm), provided that:

(1) when Y¹ is CR^(7a)R^(7b) where each R^(7a) and R^(7b) is H, then R⁶is other than H, fluoro, methoxy, unsubstituted phenyl and substitutedphenyl; and

(2) when Y¹ is NR⁸, O, S, S(O) or SO₂, then at least one of R^(5a) andR^(5b) is other than H.

In some variations of formulae (B1), (B1a), (B1d), (B1g), (B1j), (B1m),(B1s), (B1v) and (B1y)-(B1ap), at least one of X¹, X² and X³ is N. Inanother variation, one of X¹, X² and X³ is N. In one variation, X¹ is Nand each X² and X³ is independently CH or CR⁶. In another variation, X²is N and each X¹ and X³ is independently CH or CR⁶. In yet anothervariation, X³ is N and each X¹ and X² is independently CH or CR⁶. Inanother variation, two of X¹, X² and X³ is N. In one variation, each X¹and X³ is N and X is CH or CR⁶.

All variations referring to the formulae herein, such as formulae(B1a)-(B1bm), where applicable, may apply to formula (B2), the same asif each and every variation were specifically and individually listed.

In another aspect, compounds of formulae (B3)-(B4) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a), R^(2b) R^(3a), R^(3b), R^(4a), R^(4b), R^(10a) and R^(10b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R², R³,R⁴ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(5a) and R^(5b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or

when m-o are each 0, then R^(5a) and R^(7a) are taken together to form abond, or

when m is 1, and n-o are each 0, then R^(5a) and R^(7c) are takentogether to form a bond, or

when m-n are each 1, and o is 0, then R^(5a) and R^(7e) are takentogether to form a bond, or

when m-o are each 1, then R^(5a) and R^(7g) are taken together to form abond;

each m, n and o is independently 0 or 1;

each X¹, X² and X³ is independently N, CH or CR⁶;

Y¹ is CR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ isNR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d);

Y², where present, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, providedthat when Y² is NR^(8b), O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) andY³, where present, is CR^(7e)R^(7f);

Y³, where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, providedthat when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h);

Y⁴, where present, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, providedthat when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f);

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(7a) and R^(7b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7a) and R^(7b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7a) and R^(7c), where present,are taken together to form a bond;

each R^(7c) and R^(7d), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or

R^(7c) and R^(7a) are taken together to form a bond, or R^(7c) andR^(7e), where present, are taken together to form a bond;

each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f),where present, are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7e) and R^(7c) are takentogether to form a bond, or R^(7e) and R^(7g), where present, are takentogether to form a bond;

each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In a particular variation, compounds of formula (B3) have the structure:

or a salt or solvate thereof; wherein R¹, R^(5a), R^(5b), R⁶, Y¹, Y², Y³and Y⁴, where present, are defined as for formulae (B3) and, whereapplicable, any variation thereof detailed herein. That is, variationsof formulae (B3) detailed throughout, where applicable, apply toformulae (B3a)-(B3d) the same as if each and every variation werespecifically and individually listed for formulae (B3a)-(B3d).Pharmaceutically acceptable salts of compounds of formulae (B3a)-(B3d)are also provided.

All variations referring to the formulae herein, such as formulae(B3a)-(B3d), where applicable, may apply to formula (B4), the same as ifeach and every variation were specifically and individually listed.

In some embodiments, compounds of the formula (B5) are provided:

or a salt or solvate thereof; wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

each R^(5a) and R^(5b) is independently H, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted aralkyl, or R^(5a) is taken together with avicinal R^(7(a-f)) to form a bond;

Z¹ is O or CR^(7a)R^(7b);

Z² is a bond or CR^(7c)R^(7d);

Z³ is a bond or CR^(7e)R^(7f);

R⁶ is H, chloro, or substituted or unsubstituted C₁-C₈ alkyl; and

each R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) and R^(7f), when present, isindependently H, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, or substituted orunsubstituted aralkyl, or is taken together with a vicinal R^(7(a-f)) orR^(5a) to form a bond.

In one variation, compounds of the formula (B5), and salts and solvatesthereof, are embraced, provided that:

(1) when Z¹ is CR^(7a)R^(7b) and at least one of Z² and Z³ is a bond,then one or both of provisions (i) and (ii) apply: (i) R⁶ is chloro orsubstituted or unsubstituted C₁-C₈ alkyl; and (ii) at least one ofR^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) and R^(7f), whenpresent, is other than H and unsubstituted phenyl;

(2) when Z¹ is O and at least one of Z² and Z³ is a bond, then (iii) atleast one of R^(5a), R^(5b) R^(7c), R^(7d), R^(7e) and R^(7f), whenpresent, is other than H; and (iv) when one of R^(7c), R^(7d), R^(7e)and R^(7f), when present, is unsubstituted phenyl, R⁶ is chloro orsubstituted or unsubstituted C₁-C₈ alkyl; and

(3) when Z² is CR^(7c)R^(7d) and Z³ is CR^(7e)R^(7f), then one or bothof provisions (v) and (vi) apply: (v) R⁶ is chloro or substituted orunsubstituted C₁-C₈ alkyl; and (vi) at least one of R^(5a), R^(5b),R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) and R^(7f), when present, isother than H.

In another aspect, compounds of formulae (C1)-(C2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R², where present, are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(2a), where present, are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R⁴, where present, are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety or R¹ and R^(4a), where present, are taken togetherto form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—)moiety;

each R², R^(2a) and R^(2b), where present, is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy,nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R² and R¹ are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR^(2a) and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R² and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R²and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety or R^(2a) and R⁴ are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R² and avicinal R^(8(a-h)) are taken together to form a bond;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R² are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(2a) are taken togetherto form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—)moiety, or R^(3a) and R⁴ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety or R^(3a) andR^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety;

each R⁴ or R^(4a), where present, is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R⁴ and R¹ are taken together toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,or R^(4a) and R¹ are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are takentogether to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or R^(4a) and R^(2a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R⁴ and a vicinal R^(8(a-h)) are taken together to form a bond;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

each m, n, o and p is independently 0 or 1;

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol and thiol,    -   or is taken together with vicinal R², where present, to form a        bond,    -   or is taken together with vicinal R⁴, where present, to form a        bond; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In some variations, the compound is of the formula (C1), wherein R¹,R^(2a), R^(2b), R^(3a), R^(3b) R⁴, R⁵, m, n, o, p, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), R^(8h), X¹, X², X³, X⁴ and Q areas defined for formula (C1), provided that one or more of (i)-(iii)applies: (i) when none of R¹, R^(2a), R^(2b), R^(3a) R^(3b) and R⁴ aretaken together to form a ring, at least one of m, n, o and p is 1, noneof R^(8a), R^(8b) R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a ring and R⁵ is H, Q is other than carboxyl,carbonylalkoxy and unsubstituted phenyl; (ii) at least two of R¹,R^(2a), R^(2b), R^(3a), R^(3b) and R⁴ are taken together to form a ring;and (iii) at least one of m, n, o and p is 1 and at least one of R^(8a),R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) is takentogether with a vicinal R^(8(a-h)) and the carbon atoms to which theyare attached to form a substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, or substituted orunsubstituted heterocyclyl moiety.

In some variations, the compound is of the formula (C2), wherein R¹, R²,R^(3a), R^(3b), R^(4a) R^(4b), R⁵, m, n, o, p, R^(8a), R^(8b), R^(8c),R^(8d), R^(8e), R^(8f), R^(8g), R^(8h), X¹, X², X³, X⁴ and Q are asdefined for formula (C2), provided that at least one of m, n, o and p is1 and one or more of (i)-(v) applies: (i) when none of R¹, R², R^(3a),R^(3b), R^(4a) and R^(4b) are taken together to form a ring and each X¹,X², X³, and X⁴ is CH, R⁵ is an unsubstituted C₂-C₈ alkyl and Q is otherthan cyano, aminocarbonyl, dimethylamino and 4-methyl-1-piperazinyl;(ii) when none of R¹, R², R^(3a), R^(3b), R^(4a) and R^(4b) are takentogether to form a ring, each X¹, X³, and X⁴ is CH and X² is CR⁶ whereR⁶ is chloro or methoxy, R⁵ is an unsubstituted C₂-C₈ alkyl and Q isother than carbonylalkoxy and cyclobutyl; (iii) when R¹ and R² are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety and both of R^(3a) and R^(3b) are H, Q is otherthan carboxyl or carbonylalkoxy; (iv) when R¹ and R^(4a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, X² is CH or CR⁶ where R⁶ is methoxy, benzyloxy ormethylthio and both of R^(3a) and R^(3b) are H, Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted C₃-C₈ cycloalkylidene, a substituted or unsubstitutedC₃-C₈ cycloalkenylidene, or a substituted or unsubstitutedheterocyclylidene, substituted amino, aminoacyl, acyloxy, cyano, alkynylor aminocarbonylalkoxy; and (v) when R^(3a) and R^(4a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, both of R^(3b) and R^(4b) are H and only one ofm, n, o, p is 1, Q is other than carboxyl, 1-naphthyl and3,4-dimethoxyphenyl.

In specific variations, compounds of formula (C1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, X¹, X², X³, X⁴,R^(8(a-h)), m, n, o, p and Q are defined as for formula (C1) and, whereapplicable, any variation thereof detailed herein. That is, variationsof formula (C1) detailed throughout, where applicable, apply equally toany of formulae (C1-a)-(C1-c) the same as if each and every variationwere specifically and individually listed for formulae (C1-a)-(C1-c).Pharmaceutically acceptable salts of compounds of formulae (C1-a)-(C1-c)are also provided.

In specific variations, compounds of formula (C1) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³, X⁴, R^(8(a-h))and Q, where present, are defined herein and, where applicable, anyvariation thereof detailed herein. That is, variations of the formula(C1) detailed throughout, where applicable, apply equally to any offormulae (C1d)-(C1-h) the same as if each and every variation werespecifically and individually listed for formulae (C1d)-(C1-h).Pharmaceutically acceptable salts of compounds of formulae (C1d)-(C1-h)are also provided.

In another variation, compounds of formula (C1) have the structure:

or a salt or solvate thereof; wherein R⁵, R^(8(a-h)), X¹, X², X³, X⁴ andQ, where present, are defined herein and, where applicable, anyvariation thereof detailed herein. That is, variations of the formula(C1) detailed throughout, where applicable, apply equally to any offormulae (C1i)-(C1r) the same as if each and every variation werespecifically and individually listed for formulae (C1i)-(C1r). In oneembodiment, compounds of the formula (C1) are provided wherein thecompounds are of the formula (C1i)-(C1r) except that, instead of R¹ offormula (C1) being taken together with R^(2a) of formula (IA) to providecompounds of the formula (C1i)-(C1r), R¹ is taken together with R^(3a)to form a propylene moiety or a butylene moiety. In another embodiment,compounds of the formula (C1) are provided wherein the compounds are ofthe formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) beingtaken together with R^(2a) of formula (C1) to provide compounds of theformula (C1i)-(C1r), R¹ is taken together with R⁴ to form an ethylenemoiety or a propylene moiety. In a further embodiment, compounds of theformula (C1) are provided wherein the compounds are of the formula(C1i)-(C1r) except that, instead of R¹ of formula (C1) being takentogether with R^(2a) of formula (C1) to provide compounds of the formula(C1i)-(C1r), R^(2a) and R^(3a) are taken together to form an ethylenemoiety or a propylene moiety. In still a further embodiment, compoundsof the formula (C1) are provided wherein the compounds are of theformula (C1i)-(C1r) except that, instead of R¹ of formula (C1) beingtaken together with R^(2a) of formula (C1) to provide compounds of theformula (C1i)-(C1r), R^(2a) and R⁴ are taken together to form amethylene moiety or an ethylene moiety. In yet another embodiment,compounds of the formula (C1) are provided wherein the compounds are ofthe formula (C1i)-(C1r) except that, instead of R¹ of formula (C1) beingtaken together with R^(2a) of formula (C1) to provide compounds of theformula (C1i)-(C1r), R^(3a) and R⁴ are taken together to form apropylene moiety or a butylene moiety. Variations detailed throughout,where applicable, apply to such formulae the same as if each and everyvariation were specifically and individually listed. Pharmaceuticallyacceptable salts of such formulae are also provided. Pharmaceuticallyacceptable salts of compounds of formulae (C1i)-(C1r) are also provided.

All variations referring to the formulae herein, such as formulae(C1-a)-(C1r), where applicable, may apply to formula (C2), the same asif each and every variation were specifically and individually listed.

In some embodiments, compounds of the formula (CIA) have structures offormulae (G1)-(G5):

wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

each R⁴ and R⁵ is independently H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^(8c) is H, OH or substituted or unsubstituted C₁-C₈ alkyl;

R^(8d) is H or substituted or unsubstituted C₁-C₈ alkyl, and the

bond indicates the presence of either an E or Z double bondconfiguration;

Y is O or NR¹¹;

each R¹¹, R^(12a) and R^(12b) is independently H or substituted orunsubstituted C₁-C₈ alkyl;

each X¹, X³ and X⁴ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl;

provided that when the compound is of the formula (G5), D is other thanunsubstituted phenyl.

In some embodiments, the compound is of the formula (G1). In someembodiments, wherein the compound is of the formula (G2). In someembodiments, the compound is of the formula (G3). In some embodiments,the compound is of the formula (G4). In some embodiments, the compoundis of the formula (G5).

In another aspect, compounds of formulae (C3)-(C4) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) isindependently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R², R³ orR¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

R⁴ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and avicinal R^(8a), where present, are taken together to form a bond;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

each m, n, o and p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h),where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol,—S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,—S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstitutedamino, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol and thiol,    -   or is taken together with vicinal R⁴ to form a bond; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In a particular variation, compounds of formulae (C3) have thestructure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶ and R^(8(a-h)), wherepresent, and Q are defined as for formula (C3) and, where applicable,any variation thereof detailed herein. That is, variations of formula(C3) detailed throughout, where applicable, apply to formulae(C3a)-(C3e) the same as if each and every variation were specificallyand individually listed for formulae (C3a)-(C3e). Pharmaceuticallyacceptable salts of compounds of formulae (C3a)-(C3e) are also provided.

In particular variation, compounds of formula (C3) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³ and X⁴ aredefined as for formula (C3) and, where applicable, any variation thereofdetailed herein, n is 0-5, o is 0-4, p is 0-3, Z is NH, N—CH₃, O or S,and W is H, hydroxyl, halo, nitro, cyano, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted aryloxy, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino. In one particularaspect of this variation, W is H, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In one particular aspect ofthis variation, Z is S. Variations of formula (C3) detailed throughout,where applicable, apply equally to any of formulae (C3f)-(C3h), the sameas if each and every variation were specifically and individually listedfor formula (C3f)-(C3h). Pharmaceutically acceptable salts of compoundsof formulae (C3f)-(C3h) are also provided.

All variations referring to the formulae herein, such as formulae(C3a)-(C3h), where applicable, may apply to formula (C4), the same as ifeach and every variation were specifically and individually listed.

In another aspect, compounds of formulae (D1)-(D2) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R², where present, are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(2a), where present, are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R⁴, where present, are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety or R¹ and R^(4a), where present, are taken togetherto form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—)moiety;

each R², R^(2a) and R^(2b), where present, is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy,nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R² and R¹ are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR^(2a) and R¹ are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R² and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R²and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety or R^(2a) and R⁴ are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R² andR^(7a) are taken together to form a bond;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R² are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(2a) are taken togetherto form an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—)moiety, or R^(3a) and R⁴ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety or R^(3a) andR^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety;

each R⁴ or R^(4a), where present, is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R⁴ and R¹ are taken together toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,or R^(4a) and R¹ are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are takentogether to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or R^(4a) and R^(2a) are taken together to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R⁴ and R^(7a) are taken together to form a bond;

each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(5a) and R^(5b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or

when m-o are each 0, then R^(5a) and R^(7a) are taken together to form abond, or

when m is 1, and n-o are each 0, then R^(5a) and R^(7c) are takentogether to form a bond, or

when m-n are each 1, and o is 0, then R^(5a) and R^(7e) are takentogether to form a bond, or

when m-o are each 1, then R^(5a) and R^(7g) are taken together to form abond;

each m, n and o is independently 0 or 1;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

Y¹ is CR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ isNR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d);

Y², where present, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, providedthat when Y² is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³,where present, is CR^(7e)R^(7f);

Y³, where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, providedthat when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h);

Y⁴, where present, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, providedthat when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f);

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(7a) and R^(7b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7a) and R^(7b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7a) and R^(7c), where present,are taken together to form a bond, or R^(7a) and R² are taken togetherto form a bond, or R^(7a) and R⁴ are taken together to form a bond;

each R^(7c) and R^(7d), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;

each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;

each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or

R^(7g) and R^(7e) are taken together to form a bond, or R^(7g) andR^(5a) are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In one variation, the compound is of the formula (D2) where m-o are each0, provided that the compound is other thancis-4-ethyl-2,3,3a,4-tetrahydro-3-(phenylmethyl)benzo[b]pyrido[2,3,4-gh]pyrrolizin-5(1H)-oneand1,2,3,3a,4,5-hexahydro-8-methoxy-4,4-dimethylbenzo[b]pyrido[2,3,4-gh]pyrrolizine.

In another variation, the compound is of the formula (D2) where m-o areeach 0, provided that (i) when each X¹, X², X³ and X⁴ is CH, each R²,R^(3a), R^(3b), R^(4a) and R^(4b) is H, R^(5a) and R^(5b) are takentogether with the carbon to which they are attached to form a carbonylmoiety, and Y¹ is CR^(7a)R^(7b) where one of R^(7a) and R^(7b) is ethyland the other is hydrogen, R¹ is other than benzyl, and (ii) when eachX¹, X² and X⁴ is CH, X³ is CR⁶ where R⁶ is methoxy, CH, each R², R^(3a),R^(3b), R^(4a), R^(4b), R^(5a) and R^(5b) is H, and Y¹ is CR^(7a)R^(7b)where each R^(7a) and R^(7b) is methyl, R¹ is other than hydrogen.

In one variation, the compound is of the formula (D1) where m is 1 andn-o are each 0, provided that the compound is other than1,2,3,3a,5,6-hexahydro-4H-indolo[3,2,1-ij][1,6]naphthyridin-4-one.

In one variation, the compound is of the formula (D1) where m is 1 andn-o are each 0, provided that when each X¹, X², X³ and X⁴ is CH, eachR^(2a), R^(2b), R^(3a), R^(3b), R⁴, R^(5a) and R^(5b) is H, Y¹ iscarbonyl and Y² is CH₂, R¹ is other than hydrogen.

In one variation, the compound is of the formula (D2) where m is 1 andn-o are each 0, wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a),R^(5b), X¹, X², X³, X⁴, Y¹ and Y² are as defined for formula (D2),provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶.

In another variation, the compound is of the formula (D2) where m is 1and n-o are each 0, wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), X¹, X², X³, X⁴, Y¹ and Y² are as defined for formula(D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶, andwhen Y¹ is CR^(7a)R^(7b) and Y² is CR^(7c)R^(7d), at least one ofR^(5a), R^(5b), R^(7a), R^(7b), R^(7c) and R^(7d) is a group containinga cyclic moiety. In one such variation, at least one of R^(5a), R^(5b),R^(7a), R^(7b), R^(7c) and R^(7d) is selected from the group consistingof substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl. In another such variation, at least one ofR^(5a), R^(5b), R^(7a), R^(7b), R^(7c) and R^(7d) is a C₁-C₈ alkylsubstituted with a group selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl. In yet another such variation, at least oneof R^(5a), R^(5b), R^(7a), R^(7b), R^(7c) and R^(7d) is a C₂-C₈ alkenylsubstituted with a group selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl.

In one variation, the compound is of the formula (D2) where m-n are each1 and n is 0, wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a),R^(5b), X¹, X², X³, X⁴, X¹, Y² and Y³ are as defined for formula (D2),provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶.

In another variation, the compound is of the formula (D2) where m-n areeach 1 and n is 0, wherein R, R², R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), X¹, X², X³, X⁴, Y¹, Y² and Y³ are as defined for formula(D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶, andwhen Y¹ is CR^(7a)R^(7b) and Y² is CR^(7c)R^(7d), at least one ofR^(5a), R^(5b), R^(7a), R^(7b), R^(7c) and R^(7d) is a group containinga cyclic moiety. In one such variation, at least one of R^(5a), R^(5b),R^(7a), R^(7b), R^(7c) and R^(7d) is selected from the group consistingof substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl. In another such variation, at least one ofR^(5a), R^(5b), R^(7a), R^(7b), R^(7c) and R^(7d) is a C₁-C₈ alkylsubstituted with a group selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl. In yet another such variation, at least oneof R^(5a), R^(5b), R^(7a), R^(7b), R^(7c) and R^(7d) is a C₂-C₈ alkenylsubstituted with a group selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl.

In another variation, the compound is of the formula (D2) where m-n areeach 1 and n is 0, wherein R, R², R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), X¹, X², X³, X⁴, Y¹, Y² and Y³ are as defined for formula(D2), provided that at least one of X¹, X², X³ and X⁴ is N or CR⁶, andwhen Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d) and Y³ is CR^(7e)R^(7f) atleast one of R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) andR^(7f) is a group containing a cyclic moiety. In one such variation, atleast one of R^(5a), R^(5b), R^(7a), R^(7b) R^(7c), R^(7d), R^(7e) andR^(7f) is selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, and substituted or unsubstitutedheterocyclyl. In another such variation, at least one of R^(5a), R^(5b),R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) and R^(7f) is a C₁-C₈ alkylsubstituted with a group selected from the group consisting ofsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl. In yet another such variation, at least oneof R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e) and R^(7f) isa C₂-C₈ alkenyl substituted with a group selected from the groupconsisting of substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocyclyl.

In one variation, the compound is of the formula (D2) where m-o are each1, wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), X¹,X², X³, X⁴, Y¹, Y², Y³ and Y⁴ are as defined for formula (D2), providedwhen Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d), Y³ is CR^(7e)R^(7f) andY⁴ is CR^(7g)R^(7h) at least one of R^(5a), R^(5b), R^(7a), R^(7b),R^(7c), R^(7d), R^(7e), R^(7f), R^(7g) and R^(7h) is a group containinga cyclic moiety. In one such variation, at least one of R^(5a), R^(5b),R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(7f), R^(7g) and R^(7h) isselected from the group consisting of substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, and substituted or unsubstituted heterocyclyl. In anothersuch variation, at least one of R^(5a), R^(5b), R^(7a), R^(7b), R^(7c),R^(7d), R^(7e), R^(7f), R^(7g) and R^(7h) is a C₁-C₈ alkyl substitutedwith a group selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, and substituted or unsubstitutedheterocyclyl. In yet another such variation, at least one of R^(5a),R^(5b), R^(7a), R^(7b), R^(7c) R^(7d), R^(7e), R^(7f), R^(7g) and R^(7h)is a C₂-C₈ alkenyl substituted with a group selected from the groupconsisting of substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, andsubstituted or unsubstituted heterocyclyl.

In another variation, the compound is of the formula (D2) where m-o areeach 1, wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b),X¹, X², X³, X⁴, Y¹, Y², Y³ and Y⁴ are as defined for formula (D2),provided when Y¹ is CR^(7a)R^(7b), Y² is CR^(7c)R^(7d), Y³ isCR^(7e)R^(7f) and Y⁴ is CR^(7g)R^(7h) at least one of X¹, X², X³ and X⁴is N or CR⁶ and R^(5a) and R^(5b) are not taken together with the carbonto which they are attached to form a carbonyl moiety.

In specific variations, compounds of the formula (D1) have thestructure:

or a salt or solvate thereof; wherein R¹, R^(2a), R^(2b)R^(3a),R^(3b)R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R^(7(a-h)), X¹, X², X³, X⁴,Y¹, Y², Y³ and Y⁴, where present, are defined as for formula (D1) and,where applicable, any variation thereof detailed herein. That is,variations of formula (D1) detailed throughout, where applicable, applyto formulae (D1a)-(D1bm) the same as if each and every variation werespecifically and individually listed for formulae (D1a)-(D1bm).Pharmaceutically acceptable salts of compounds of formulae (D1a)-(D1bm)are also provided.

All variations referring to the formulae herein, such as formulae(D1a)-(D1bm), where applicable, may apply to formula (D2), the same asif each and every variation were specifically and individually listed.

In another aspect, compounds of formulae (D3)-(D4) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(10a) and R^(10b) isindependently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R², R³ orR¹⁰ to form a carbonyl moiety or a cycloalkyl moiety;

R⁴ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ andR^(7a) are taken together to form a bond;

each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(5a) and R^(5b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or

when m-o are each 0, then R^(5a) and R^(7a) are taken together to form abond, or

when m is 1, and n-o are each 0, then R^(5a) and R^(7c) are takentogether to form a bond, or

when m-n are each 1, and o is 0, then R^(5a) and R^(7e) are takentogether to form a bond, or

when m-o are each 1, then R^(5a) and R^(7g) are taken together to form abond;

each m, n and o is independently 0 or 1;

each X¹, X², X³ and X⁴ is independently N, CH or CR⁶;

Y¹ is CR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ isNR⁸, O, S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d);

Y², where present, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, providedthat when Y² is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³,where present, is CR^(7e)R^(7f);

Y³, where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, providedthat when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h);

Y⁴, where present, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, providedthat when Y⁴ is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f);

R⁶ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(7a) and R^(7b) is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7a) and R^(7b) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7a) and R^(7c), where present,are taken together to form a bond, or R^(7a) and R⁴ are taken togetherto form a bond;

each R^(7c) and R^(7d), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;

each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;

each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and

R⁸ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.

In particular variation, compounds of formulae (D3) have the structure:

or a salt or solvate thereof; wherein R¹, R^(5a), R^(5b), R⁶, Y¹, Y², Y³and Y⁴, where present, are defined as for formulae (D3) and, whereapplicable, any variation thereof detailed herein. That is, variationsof formulae (D3) detailed throughout, where applicable, apply toformulae (D3a)-(D3d) the same as if each and every variation werespecifically and individually listed for formulae (D3a)-(D3d).Pharmaceutically acceptable salts of compounds of formulae (D3a)-(D3d)are also provided.

All variations referring to the formulae herein, such as formulae(D3a)-(D3d), where applicable, may apply to formula (D4), the same as ifeach and every variation were specifically and individually listed.

In one variation of formulae (A1)-(A4) or (B1)-(B2), or any variationtherefrom, at least one of X¹, X² and X³ is N. In another variation, oneof X¹, X² and X³ is N. In one variation, X¹ is N and each X² and X³ isindependently CH or CR⁶. In another variation, X² is N and each X¹ andX³ is independently CH or CR⁶. In yet another variation, X³ is N andeach X¹ and X² is independently CH or CR⁶. In another variation, two ofX¹, X² and X³ is N. In one variation, each X¹ and X³ is N and X² is CHor CR⁶.

In another variation of formulae (C1)-(C4) or (D1)-(D4), or anyvariation therefrom, at least one of X¹, X², X³ and X⁴ is N. In anothervariation, one of X¹, X² and X³ is N. In one variation, X¹ is N and eachX², X³ and X⁴ is independently CH or CR⁶. In another variation, X² is Nand each X¹, X³ and X⁴ is independently CH or CR⁶. In yet anothervariation, X³ is N and each X¹, X² and X⁴ is independently CH or CR⁶. Inyet another variation, X⁴ is N and each X¹, X² and X³ is independentlyCH or CR⁶. In another variation, two of X¹, X², X³ and X⁴ is N. In onevariation, each X¹ and X³ is N, and X² and X⁴ is CH or CR⁶. In anothervariation, each X² and X⁴ is N, and X¹ and X³ is CH or CR⁶. In anothervariation, each X¹ and X⁴ is N, and X² and X³ is CH or CR⁶.

In one variation of formulae (A1)-(A4) or (C1)-(C4), the chaincomprising R^(8a), R^(8b) R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), R^(8h)and Q is selected from the following structures:

or a salt or solvate thereof, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g), R^(8h) and Q are as defined herein and ring Acomprises a substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl group.

In another variation of formulae (A1)-(A4) or (C1)-(C4), the chaincomprising R^(8a), R^(8b) R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), R^(8h)and Q is selected from the following structures:

or a salt or solvate thereof, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g), R^(8h) and Q are as defined herein and ring Acomprises a substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl group. In a particular variation, when o and p are each 0,the chain comprising R^(8a), R^(8b), R^(8c), R^(8d) and Q is selectedfrom the following structures:

In a particular variation, where ring A depicted above comprises asubstituted or unsubstituted C₃-C₈ cycloalkenyl, the double-bond of thecycloalkenyl ring is at a position other than in the linear chain. Forexample, if the carbon atoms bearing R^(8a) and R^(8c) are part of asubstituted or unsubstituted C₃-C₈ cycloalkenyl ring, e.g., ring Adepicted above, then the carbon atoms bearing R^(8a) and R^(8c) areconnected by a single bond.

In certain embodiments, compounds are provided wherein R¹ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. Inspecific embodiments, R¹ is a substituted or unsubstituted C₁-C₈ alkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclylor substituted or unsubstituted aryl. In more specific embodiments, R¹is an unsubstituted C₁-C₈ alkyl such as methyl and cyclopropyl.

In certain embodiments, compounds are provided where R¹ is selected fromthe following moieties:

In certain compounds described herein, each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b) are takentogether to form a carbonyl moiety. In specific embodiments, each R^(2a)and R^(2b) is independently H or fluoro. In another specific embodiment,R^(2a) and R^(2b) are both H. In a further specific embodiment, R^(2a)and R^(2b) are both H and R^(3a) and R^(3b) are both H.

In certain compounds described herein, each R^(3a) and R^(3b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy, nitro or R^(3a) and R^(3b) are taken together to forma carbonyl moiety. In specific embodiments, each R^(3a) and R^(3b) isindependently H, methyl, fluoro or R^(3a) and R^(3b) are taken togetherto form a carbonyl moiety. In a specific embodiment, R^(3a) and R^(3b)are both H.

In certain compounds, each R⁴, R^(4a) and R^(4b), where present, isindependently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano,hydroxyl, alkoxy, nitro or R^(4a) and R^(4b) are taken together to forma carbonyl moiety. In specific embodiments, each R^(4a) and R^(4b) isindependently H, halo, hydroxyl or methyl or R^(4a) and R^(4b) are takentogether to form a carbonyl moiety. In another specific embodiment,R^(4a) and R^(4b) are both H. In a further specific embodiment, R^(4a)and R^(4b) are both H and R^(2a), R^(2b), R^(3a) and R^(3b) are each H.

In certain compounds described herein, each R^(10a) and R^(10b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy, nitro or R^(10a) and R^(10b) are taken together toform a carbonyl moiety. In specific embodiments, each R^(10a) andR^(10b) is independently H, methyl, fluoro or R^(10a) and R^(10b) aretaken together to form a carbonyl moiety. In a specific embodiment,R^(10a) and R^(10b) are both H.

In certain compounds, each X¹, X², X³ and X⁴, where present, isindependently N, CH or CR⁶. In certain embodiments, each X¹, X², X³ andX⁴, where present, is CH or CR⁶, such that the ring comprising X¹, X²,X³ and X⁴, where present, is an optionally substituted phenyl ring. Inspecific embodiments, X² is CR⁶ where R⁶ is halo or alkyl and X¹ and X³are each CH. In other embodiments, one of X¹, X², X³ and X⁴ is N, andthe others are CH or CR⁶, such that the ring comprising X¹, X², X³ andX⁴ is an optionally substituted pyridine ring. In further embodiments,two of X¹, X², X³ and X⁴ are N, and the other is CH or CR⁶, such thatthe ring comprising X¹, X², X³ and X⁴ is an optionally substitutedpyrimidine or pyrazine ring.

In certain compounds, each R⁶, where present, is independently hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl. In one variation, at least one of X¹-X³ isCR⁶ where R⁶ is halo. In a particular variation, one of X¹-X³ is CR⁶where R⁶ is chloro and the others are CH. In a specific variation, X¹and X³ are each CH and X² is CR⁶ where R⁶ is chloro.

In certain embodiments, each R⁶, where present, is independentlyhydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, alkylsulfonylamino oracyl. In further embodiments, each R⁶, where present, is independentlyhydroxyl, halo, C₁-C₄ perhaloalkyl, substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or C₁-C₄ alkoxy; or in still a further variation, each R⁶,where present, is independently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄perhaloalkyl.

In specific embodiments, the ring comprising X¹, X², X³ and X⁴, wherepresent, is a phenyl, pyridyl, pyrimidinyl or pyrazinyl ring, optionallysubstituted with 0-3 R⁶ groups (i.e., (R⁶)_(n) where n is 0, 1, 2 or 3).In some such embodiments, n is 1, 2 or 3 and each R⁶ is independentlyhalo, methyl or CF₃.

In compounds of formulae (B1-B4) and (D1-D4), and variations thereof, atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino. In one variation,compounds are provided where at least one of R^(5a), R^(5b), R^(7(a-h))or Q, where present, is a substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl orsubstituted or a unsubstituted heterocyclyl. In certain embodiments, atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is asubstituted or unsubstituted 5- or 6-membered aryl or heteroaryl. Insome such embodiments, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q,where present, is a substituted or unsubstituted phenyl, pyridyl orpyrimidinyl ring. When at least one of R^(5a), R^(5b), R^(7(a-h)) or Q,where present, is substituted, it is frequently substituted with from1-3 substituents selected from group consisting of halo, C₁-C₄ alkyl,C₁-C₄ perhaloalkyl, and C₁-C₄ alkoxy.

In a particular variation, compounds of formulae (B1-B4) and (D1-D4),and variations thereof, have at least one of R^(5a), R^(5b), R^(7(a-h))or Q, where present, is a substituted heteroaryl, a monosubstituted arylgroup substituted with a chloro or alkyl group or a di- ortri-substituted aryl moiety. For instance, at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, in one variation is selectedfrom the group consisting of 4-methoxy-3-fluorophenyl,3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl,3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl,6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl and pyrimidinyl. In one aspect, at least oneof R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a substitutedpyridyl such as 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and5-trifluoromethyl-3-pyridyl.

In some embodiments, R¹ is a substituted or unsubstituted C₁-C₈ alkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclylor substituted or unsubstituted aryl; each R^(2a) and R^(2b) isindependently H, methyl, fluoro or R^(3a) and R^(3b) are taken togetherto form a carbonyl moiety; each R^(4a) and R^(4b) is independently H orfluoro; and each R^(3a) and R^(3b) is independently H, halo, hydroxyl ormethyl or R^(2a) and R^(2b) are taken together to form a carbonylmoiety. In particular variations, R¹ is an unsubstituted C₁-C₈ alkyl andR^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are each H. In still afurther variation, R¹ is an unsubstituted C₁-C₈ alkyl, R^(2a), R^(2b),R^(3a), R^(3b) R^(4a) and R^(4b) are each H and at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, is selected from the groupconsisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl,4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl,2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl,4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl,6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl andpyrimidinyl. In still a further variation, R¹ is an unsubstituted C₁-C₈alkyl, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are each H andX² is CR⁶ where R⁶ is chloro. In yet a further variation, R¹ is anunsubstituted C₁-C₈ alkyl, R^(2a), R^(2b) R^(3a), R^(3b), R^(4a) andR^(4b) are each H, X² is CR⁶ where R⁶ is chloro and at least one ofR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a substituted orunsubstituted aryl or a substituted or substituted heteroaryl. In onesuch variation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a substituted phenyl.

In certain embodiments, compounds of formulae (A1)-(A4) or (C1)-(C4),and variations thereof, are provided where Q is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxyor acylamino. In one variation, compounds are provided where Q is asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl or substituted or a unsubstitutedheterocyclyl. In certain embodiments, Q is a substituted orunsubstituted 5- or 6-membered aryl or heteroaryl. In some suchembodiments, Q is a substituted or unsubstituted phenyl, pyridyl orpyrimidinyl ring. When Q is substituted, it is frequently substitutedwith from 1-3 substituents selected from group consisting of halo, C₁-C₄alkyl, C₁-C₄ perhaloalkyl, and C₁-C₄ alkoxy.

In a particular variation of compounds of formulae (A1)-(A4) or(C1)-(C4), and variations thereof, Q is a substituted heteroaryl, amono-substituted aryl group substituted with a chloro or alkyl group ora di- or tri-substituted aryl moiety. For instance, each Q in onevariation is independently selected from the group consisting of4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 2,4,6-trifluorophenyl, 4-chlorophenyl,4-methylphenyl, 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl and pyrimidinyl. In one aspect, Q is asubstituted pyridyl such as 6-methyl-3-pyridyl,6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.

In particular embodiments, each X¹, X², X³ and X⁴, where present, is CHor CR⁶. In other embodiments, at least one of X¹, X², X³ and X⁴, wherepresent, is N. Another variation provides a compound where at least twoof X¹, X², X³ and X⁴, where present, are N. A further variation providesa compound where two of X¹, X², X³ and X⁴, where present, are N and oneof X¹, X², X³ and X⁴, where present, is CH or CR⁶. Compounds where oneof X¹, X², X³ and X⁴, where present, is N and two of X¹, X², X³ and X⁴,where present, are CH or CR⁶ are also embraced by this invention.

In one variation, compounds of formulae (A1)-(A4) and (B1)-(B4), andvariations thereof, are provided wherein the ring comprising X¹, X² andX³ is an aromatic moiety selected from the following structures:

where each R⁶ is as defined. In a particular variation, each R⁶ isindependently hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or amino,alkylsulfonylamino or acyl. In a further variation, each R⁶ isindependently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, orC₁-C₄ alkoxy.

In a further variation, compounds of formulae (A1)-(A4) and (B1)-(B4),and variations thereof, are provided, wherein the ring comprising X¹, X²and X³ is an aromatic moiety selected from the following structures:

wherein R⁶ is as defined herein; or in a particular variation, where R⁶is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl,or C₁-C₄ alkoxy.

In a further variation, compounds of formulae (A1)-(A4) and (B1)-(B4),and variations thereof, are provided wherein the ring comprising X¹, X²and X³ is an aromatic moiety selected from the following structures:

In another variation, compounds of formulae (C1)-(C4) and (D1)-(D4), andvariations thereof, are provided wherein the ring comprising X¹, X², X³,and X⁴ is an aromatic moiety selected from the following structures:

where each R⁶ is as defined. In a particular variation, each R⁶ isindependently hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or amino,alkylsulfonylamino or acyl. In a further variation, each R⁶ isindependently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, orC₁-C₄ alkoxy.

In a further variation, of formulae (C1)-(C4) and (D1)-(D4), andvariations thereof, are provided, wherein the ring comprising X¹, X², X³and X⁴ is an aromatic moiety selected from the following structures:

wherein R⁶ is as defined herein; or in a particular variation, where R⁶is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl,or C₁-C₄ alkoxy.

In a further variation, compounds of formulae (C1)-(C4) and (D1)-(D4),and variations thereof, are provided wherein the ring comprising X¹, X²,X³ and X⁴ is an aromatic moiety selected from the following structures:

Any formula detailed herein, where applicable, may in one variation haveX¹, X², X³ and X⁴, where present, taken together to provide an aromaticmoiety detailed herein above. It is understood that by “whereapplicable” it is intended that in one variation such X¹, X², X³ and X⁴groups are taken together to provide a moiety hereinabove if the formulaencompasses such a structure. For example, if a given formula does notencompass structures wherein X¹, X², X³ and X⁴ groups are taken togetherprovide a pyridyl moiety, then a pyridyl moiety as detailed hereinaboveis not applicable to that particular formula, but remains applicable toformulae that do encompass structures where X¹, X², X³ and X⁴ groups aretaken together provide a pyridyl moiety.

In another embodiment, a compound of the invention is provided, whereinX¹-X⁴, where present, are as defined or as detailed in any variationherein, where R¹ is H, substituted or unsubstituted C₁-C₈ alkyl, acyl,acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl. In a furtherembodiment, a compound of the invention is provided, wherein X¹-X⁴ areas defined or as detailed in any variation herein, where R¹ is asubstituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy,substituted or unsubstituted heterocyclyl or substituted orunsubstituted aryl. In a particular variation, a compound of theinvention is provided, wherein X¹-X⁴ are as defined or as detailed inany variation herein, where R¹ is methyl, ethyl, cyclopropyl, propylate,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

When any carbon of the preceding formulae bearing R^(2a) and R^(2b), orR^(3a) and R^(3b), or R^(4a) and R^(4b), or R^(10a) and R^(10b) isoptically active, it may be in the (R)- or (S)-configuration andcompositions comprising substantially pure (R) or (S) compound ormixtures thereof in any amount are embraced by this invention.

In one variation, compounds of formulae (A1) and (B1), and variationsthereof, are provided wherein the ring comprising N, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety selected from thefollowing structures:

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are asdefined, and p is 1 or 2.

In another variation, compounds of formulae (A2) and (B2), andvariations thereof, are provided wherein the ring comprising N, R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety selected from thefollowing structures:

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are asdefined, and p is 1 or 2.

In another variation, compounds of formulae (A1) and (B1), andvariations thereof, are provided wherein the ring comprising N, R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety selected from thefollowing structures:

In another variation, compounds of formulae (A2) and (B2), andvariations thereof, are provided wherein the ring comprising N, R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety selected from thefollowing structures:

In any one of the variations of compounds of the formulae describedherein, all stereoisomers are intended. For example, the ring can beeither

Where more than one stereocenter is present, it is understood that allsuch stereoisomers are intended. For example, a compound having twostereocenters may be present in the (S),(S); (S),(R); (R),(R); and(R),(S) forms. Compositions comprising a single stereoisomer or mixturesof more than one stereoisomer are also intended. Compositions comprisinga mixture of stereoisomers in any ratio are embraced, including mixturesof two or more stereochemical forms of a compound of the invention inany ratio, such that racemic, non-racemic, enantioenriched and scalemicmixtures of a compound are embraced.

In some embodiments of formulae (A1) and (B1), and variations thereof,are provided, the ring comprising N, R^(2a), R^(2b), R^(3a), R^(3b),R^(4a) and R^(4b) is a moiety selected from the following structures:

where R¹ in the structures above is as defined or as detailed in anyparticular variation detailed herein. In some embodiments, the ring isof the formula:

where R¹ is as detailed in any particular variation detailed herein. Anyformula detailed herein, where applicable, may in one variation have aring according to the structures above.

Compounds according to formulae (A1)-(A4) or (C1)-(C4), or any variationthereof, in one variation are provided where m, n, o, p, and R^(8(a-h)),if present and where applicable, are taken together to form a moietyselected from the group consisting of the structures:

When the above structures are applied to formulae (A1)-(A4) or(C1)-(C4), or any variation thereof, herein, it is understood that m, n,o, p and R^(8(a-h)), where applicable, are taken together to form theforegoing moieties, including but not limited to, the structures of thisparagraph. Likewise, any formula detailed herein, where applicable, mayin one variation have m, n, o, p and R^(8(a-h)), if present, takentogether to form a moiety as detailed herein above, including but notlimited to, the structures of this paragraph. It is understood that by“where applicable” it is intended that in one variation such m, n, o, pand R^(8(a-h)) groups, if present, are taken together to provide amoiety hereinabove if the formula encompasses such a structure. Forexample, if a given formula does not encompass structures wherein m, n,o, p and R^(8(a-h)) groups, if present, are taken together to provide a—CH₂CH₂— moiety, then a —CH₂CH₂— moiety as detailed hereinabove is notapplicable to that particular formula, but remains applicable toformulae that do encompass structures where m, n, o, p and R^(8(a-h))groups, if present, are taken together to provide a —CH₂CH₂— moiety.

In one aspect, at least one of R^(8(a-h)) is a C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety.

Compounds according to formulae (A1)-(A4) or (C1)-(C4), or any variationthereof, where applicable, in one variation are provided where one ormore of R^(8(a-h)) and the carbon to which it is attached, together witha vicinal R⁸ and the carbon to which it is attached, form a moietyselected from the group consisting of the structures, each of which maybe optionally substituted, where each R⁸ is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy or carbonylalkoxy:

In another variation, any double bond, if present in the cycloalkenylring, may also be present at any location in the ring, where chemicallyfeasible, as exemplified above for the cyclopropenyl moiety.

In certain compounds where applicable in one variation, at least one ofR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, which maybe but is not limited to a substituted or unsubstituted pyridyl, phenyl,pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenylgroup. In one variation, a compound of the invention is provided, whereat least one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is asubstituted or unsubstituted phenyl or pyridyl group. In a particularvariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a phenyl or pyridyl group substituted with at least onemethyl, trifluoromethyl, methoxy or halo substituent. In anothervariation, a compound of the invention is provided, where at least oneof R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a pyridyl, phenyl,pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenylgroup substituted with at least one substituted or unsubstituted C₁-C₄alkyl, C₁-C₄ alkoxy, halo or C₁-C₄ perhaloalkyl moiety.

In still another variation, compounds are provided, where at least oneof R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a substituted orunsubstituted C₃-C₈ cycloalkyl or a substituted or unsubstitutedheterocyclyl. In another variation, at least one of R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is a substituted or unsubstituted C₃-C₈cycloalkyl or a substituted or unsubstituted heterocyclyl. In yetanother variation, a compound of the invention is provided where atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is asubstituted or unsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl,pyrrolidinyl or thiomorpholinyl group. In a particular variation, atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is apyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinylgroup substituted with at least one methyl, CF₃, methoxy or halo group.

In one variation, compounds are provided where at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, is an unsubstituted cycloalkylor an unsubstituted heterocyclyl. In another variation, at least one ofR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is an unsubstitutedC₃-C₈ cycloalkyl or an unsubstituted heterocyclyl. In another variation,a compound of the invention is provided where at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, is a substituted orunsubstituted cyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl,cyclopentyl or pyrrolidinyl moiety. In yet another variation, a compoundof the invention is provided where at least one of R^(5a), R^(5b)R^(7(a-h)) or Q, where present, is a substituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety substituted with at least one carbonyl, hydroxymethyl, methyl orhydroxyl group. R^(5a), R^(5b), R^(7(a-h)) or Q, where present, groupsmay be attached to the parent structure at any available position on theR^(5a), R^(5b), R^(7(a-h)) or Q moiety. Thus, although specificattachment points for certain R^(5a), R^(5b), R^(7(a-h)) or Q moietiesare depicted herein, it is understood that such R^(5a), R^(5b),R^(7(a-h)) or Q moieties, may also be connected to the parent structureat any available position. For example, if a monofluoro-phenyl isdepicted herein, it is understood that each of the availablemono-fluoro-phenyl moieties are intended, e.g., 2-fluoro-phenyl,3-fluoro-phenyl and 4-fluoro-phenyl. It is also understood that anyformula detailed herein, where applicable, may in one variation have aR^(5a), R^(5b), R^(7(a-h)) or Q, where present, moiety as detailedherein and below.

In still another variation, a compound of the invention is providedwhere at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, isa moiety selected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl(C₁-C₈), perhaloalkoxy (C₁-C₈), substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl,substituted or unsubstituted heterocyclyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, the R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is substituted with no more than one R⁹group. In another variation, the R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is substituted with only one R⁹ group. In one variation, theR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is substituted with twoR⁹ groups. In a further variation, at least one of R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is selected from the aromatic structuresdetailed where the residue has the moiety (R⁹)₀ such that the R^(5a),R^(5b), R^(7(a-h)) or Q either contains no R⁹ functionality or a moietyof the formula N—R⁹. In one variation, at least one of R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is selected from the aromatic structuresdetailed where the R^(5a), R^(5b), R^(7(a-h)) or Q, where present, issubstituted with no more than one R⁹ group. In another variation, theR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is substituted with onlyone R⁹ group. In one variation, the R^(5a), R^(5b), R^(7(a-h)) or Q,where present, is substituted with two R⁹ groups. In a furthervariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is selected from the aromatic structures detailed where theresidue has the moiety (R⁹)₀ such that the R^(5a), R^(5b), R^(7(a-h)) orQ, where present, either contains no R⁹ functionality or a moiety of theformula N—R⁹.

In another variation, a compound of the invention is provided where atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a moietyselected from the structures:

wherein R⁹ is connected to the R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, ortho or para to the position at which R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is connected to the carbon bearing theR^(5a), R^(5b) R^(7(a-h)) or Q, where present. In a particularvariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a structure of the formula

and R⁹ is connected to the R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, para to the position at which the R^(5a), R^(5b), R^(7(a-h)) orQ, where present, is connected to the carbon bearing the R^(5a), R^(5b),R^(7(a-h)) or Q, where present. In another particular variation, atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is astructure of the formula

where each R⁹ is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is provided where atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a moietyselected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, the R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is substituted with no more than one R⁹group. In another variation, at least one of R^(5a), R^(5b), R^(7(a-h))or Q, where present, is substituted with only one R⁹ group. In yetanother variation, at least one of R^(5a), R^(5b) R^(7(a-h)) or Q, wherepresent, is substituted with two R⁹ groups. In a particular variation,at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, isselected from the carbocyclic and heterocyclic structures detailed wherethe residue has the moiety (R⁹)₀ such that at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, either contains no R⁹functionality or a moiety of the formula N—R⁹.

In any structure or variation detailed herein containing an R⁹ group, inone variation, each R⁹ is independently a substituted or unsubstitutedC₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation,each R⁹ is independently methyl, —CH₂OH, isopropyl, halo,trifluoromethyl or hydroxyl.

In another variation, a compound of the invention is provided where atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a moietyselected from the structures:

In another variation, a compound of the invention is provided where atleast one of R^(5a) R^(5b), R^(7(a-h)) or Q, where present, is a moietyselected from the structures:

In another variation, a compound of the invention is provided where atleast one of R^(5a) R^(5b), R^(7(a-h)) or Q, where present, is a moietyselected from the structures:

In yet another variation, a compound of the invention is provided whereat least one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is amoiety selected from the structures:

In any of the variations described herein for R^(5a), R^(5b),R^(7(a-h)), or Q, where present, only one point of attachment of eachmoiety to the parent structure may be depicted, however it is understoodthat the moiety may be attached to the parent structure at any position,where chemically feasible.

In another variation, a compound of the invention is provided where atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is asubstituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino moiety. In a particularvariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is an unsubstituted amino. In another variation, at least oneof R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a substitutedamino of the formula —N(C₁-C₈ alkyl)₂ such as the moiety —N(Me)₂ or—N(CH₃)(CH₂CH₃). In another variation, at least one of R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is a substituted amino of the formula—N(H)(cycloalkyl or substituted cycloalkyl), such as a moiety of theformula:

In another variation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q,where present, is independently a substituted amino of the formula—N(H)(aryl or substituted aryl), such as a moiety of the formula:

The invention also embraces compounds where at least one of R^(5a),R^(5b), R^(7(a-h)) Or Q, where present, is an aminoacyl moiety. In onevariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is an aminoacyl group where at least one of R_(a) and R_(b) isH, such as when at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is of the formula —NHC(O)R_(b). In one variation, at least oneof R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is an aminoacylmoiety selected from the group consisting of: —NHC(O)-heterocyclyl,—NHC(O)— substituted heterocyclyl, —NHC(O)-alkyl, —NHC(O)-cycloalkyl,—NHC(O)-aralkyl and —NHC(O)-substituted aryl. In another variation, atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is anaminoacyl moiety selected from the group consisting of: —NHC(O)—C₅-C₇heterocyclyl, —NHC(O)—C₁-C₆ alkyl, —NHC(O)—C₃-C₇ cycloalkyl,—NHC(O)—C₁-C₃ aralkyl and —NHC(O)-substituted phenyl. In a particularvariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a moiety of the formula:

In one variation, a compound of the invention is provided where at leastone of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is acyloxy.

In one variation, a compound of the invention is provided where at leastone of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is acarbonylalkoxy moiety. In one variation, at least one of R^(5a) R^(5b),R^(7(a-h)) or Q, where present, is a carbonylalkoxy moiety of theformula —C(O)—O—R where R is H, alkyl, substituted alkyl or alkaryl. Inone variation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a carbonylalkoxy moiety of the formula —C(O)—O—C₁-C₆ alkyl.In a particular variation, at least one of R^(5a), R^(5b), R^(7(a-h)) orQ, where present, is a carbonylalkoxy moiety of the formula—C(O)—O—C₂H₅. In one variation, at least one of R^(5a), R^(5b),R^(7(a-h)) or Q, where present, is a carbonylalkoxy moiety selected fromthe group consisting of: —C(O)—O—C₁-C₁₀alkyl, —C(O)—O—C₁-C₃alkaryl,—C(O)—O—C₁-C₃substituted alkyl and —C(O)—OH. In another variation,R^(5a), R^(5b) R^(7(a-h)) or Q, where present, is —C(O)—O—C₁-C₆alkyl. Ina particular variation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q,where present, is a moiety of the formula:

In another variation, a compound of the invention is provided where atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is anaminocarbonylalkoxy moiety. In one variation, at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, is an aminocarbonylalkoxy moietyof the formula —NHC(O)—O—R_(b). In another variation, at least one ofR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is anaminocarbonylalkoxy moiety of the formula —NHC(O)—O—R_(b) where R_(b) isa substituted alkyl group. In a particular variation, at least one ofR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a moiety of theformula —NH—C(O)—O—CH₂—CCl₃.

The invention also embraces compounds where at least one of R^(5a),R^(5b), R^(7(a-h)) Or Q, where present, is an acylamino moiety. In onevariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is an acylamino group where at least one of R_(a) and R_(b) isH, such as when R^(5a) R^(5b), R^(7(a-h)) or Q, where present, is of theformula —C(O)N(H)(R_(b)). In another variation, at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, is an acylamino group where bothR_(a) and R_(b) are alkyl. In one variation, at least one of R^(5a),R^(5b), R^(7(a-h)) or Q, where present, is an acylamino moiety selectedfrom the group consisting of: —C(O)—N(H)(alkyl), —C(O)—N(alkyl)₂,—C(O)—N(H)(aralkyl) and —C(O)—N(H)(aryl). In another variation, at leastone of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is an acylaminomoiety selected from the group consisting of: —C(O)—N(H)₂,—C(O)—N(H)(C₁-C₈ alkyl), —C(O)—N(C₁-C₆ alkyl)₂ and—C(O)—N(H)(C₁-C₃aralkyl). In a particular variation, at least one ofR^(5a), R^(5b), R^(7(a-h)) or Q, where present, is a moiety of theformula:

In a further variation, a compound of the invention is provided where R¹is an unsubstituted alkyl, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) andR^(4b) are each H, each X¹, X² and X³ and X⁴, where present, isindependently N or CH, and at least one of R^(5a), R^(5b), R^(7(a-h)) orQ, where present, is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, including but not limited to a substituted orunsubstituted phenyl or pyridyl group. Where at least one of R^(5a),R^(5b) R^(7(a-h)) or Q, where present, is a substituted phenyl orpyridyl group, in one variation it is substituted with at least onemethyl or halo group.

In yet a further variation, a compound of the invention is providedwhere R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl; each R^(2a) and R^(2b) is independently H,unsubstituted C₁-C₈ alkyl or halo; each R^(3a) and R^(3b) isindependently H or halo; each X¹, X² and X³ and X⁴, where present, is CHor CR⁶, where R⁶ is as defined or as detailed in a particular variation,R⁶ is halo, pyridyl, methyl or trifluoromethyl; R^(4a) and R^(4b) areboth H, and at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, including but not limited to a substituted orunsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl,furanyl, pyrrolyl or thiophenyl group. In a particular variation, atleast one of R^(5a), R^(5b), R^(7(a-h)) or Q, where present, is apyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolylor thiophenyl group substituted with at least one substituted orunsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety. In onevariation, a compound of the variation detailed herein is providedwherein R¹ is propylate, methyl, ethyl, cyclopropyl, trifluoromethyl,isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal,1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, a compound of the invention is providedwhere R¹ is a substituted or unsubstituted C₁-C₈ alkyl; each R^(2a),R^(2b), R^(3a) and R^(3b) is independently H or halo; each R⁶ isindependently halo, C₁-C₈ perhaloalkyl, substituted or a unsubstitutedC₁-C₈ alkyl; and at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, is a substituted or unsubstituted cyclohexyl, morpholinyl,piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. Theinvention also embraces a compound where R¹ is a methyl; at least one ofX¹, X² and X³ and X⁴, where present, is CR⁶, and each R⁶ isindependently halo, methyl or trifluoromethyl. The invention embracescompounds where at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, in any variation detailed is substituted with at least onecarbonyl, hydroxymethyl, methyl or hydroxyl group, to the extent suchsubstituent makes chemical sense.

In a particular variation, a compound is provided where R¹ is asubstituted or unsubstituted C₁-C₈ alkyl; each R^(2a) and R^(2b) isindependently H, a substituted or unsubstituted C₁-C₈ alkyl or R^(2a)and R^(2b) are taken together to form a carbonyl moiety; R^(3a) andR^(3b) are both H; each R^(4a) and R^(4b) is independently H, halo, asubstituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxy or R^(4a) andR^(4b) are taken together to form a carbonyl moiety, provided that atleast one of R^(4a) and R^(4b) is other than H. In one aspect of thisvariation, at least one of R^(5a), R^(5b), R^(7(a-h)) or Q, wherepresent, may be a substituted or unsubstituted pyridyl, phenyl,pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group. Inanother aspect of this variation, at least one of R^(5a) R^(5b),R^(7(a-h)) or Q, where present, is a pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with atleast one methyl or halo group. In yet another aspect of this variation,each X¹, X² and X³ and X⁴, where present, is independently CH or CR⁶ andeach R⁶ is independently halo or methyl.

In a particular variation, a compound is provided wherein R¹, R^(2a),R^(2b), R^(3a), R^(3b), R^(10a) R^(10b), R^(11a) and R^(11b) are takentogether to form a ring selected from the structures:

where R¹ in the structures above is as defined herein.

In one embodiment, the invention relates to compounds of Tables 1-4, anduses thereof.

In another embodiment, the invention relates to Compound nos. A1 toA160, B1 to B242, C1 to C136 and D1 to D266, and uses thereof.

In another embodiment, the invention relates to Compound nos. A1 to A18,A43 to A44, B1 to B16, B156 to B165, B210 to B211, C43 to C48, and D1 toD12, and uses thereof.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable.

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the invention aredepicted in the tables below. It is understood that in one aspect, anyof the compounds may be used in the methods detailed herein, including,where applicable, intermediate compounds that may be isolated andadministered to an individual.

The compounds depicted herein may be present as salts even if salts arenot depicted and it is understood that the invention embraces all saltsand solvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan. In some embodiments, the salts of the compounds of theinvention are pharmaceutically acceptable salts. Where one or moretertiary amine moiety is present in the compound, the N-oxides are alsoprovided and described.

Where tautomeric forms may be present for any of the compounds describedherein, each and every tautomeric form is intended even though only oneor some of the tautomeric forms may be explicitly depicted. For example,when a 2-hydroxypyridyl moiety is depicted, the corresponding 2-pyridonetautomer is also intended. The tautomeric forms specifically depictedmay or may not be the predominant forms in solution or when usedaccording to the methods described herein.

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. In onevariation, “substantially pure” intends a composition that contains nomore than 35% impurity, wherein the impurity denotes a compound otherthan the compound comprising the majority of the composition or a saltthereof. Taking compound 1 as an example, a composition of substantiallypure compound 1 intends a composition that contains no more than 35%impurity, wherein the impurity denotes a compound other than compound 1or a salt thereof. In one variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsno more than 25% impurity. In another variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 20% impurity. In still anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 10%impurity. In a further variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsor no more than 5% impurity. In another variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 3% impurity. In still anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 1%impurity. In a further variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsor no more than 0.5% impurity. In yet other variations, the compositionof “substantially pure” compound contains no more than 15% or preferablyno more than 10% or more preferably no more than 5% or even morepreferably no more than 3% and most preferably no more than 1% impurity,which impurity may be the compound in a different stereochemical form.For instance, a composition of substantially pure (S) compound meansthat the composition contains no more than 15% or no more than 10% or nomore than 5% or no more than 3% or no more than 1% of the (R) form ofthe compound.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

Kits comprising a compound of the invention, or a salt or solvatethereof, and suitable packaging are provided. In one embodiment, a kitfurther comprises instructions for use. In one aspect, a kit comprises acompound of the invention, or a salt or solvate thereof, andinstructions for use of the compounds in the treatment of a disease orcondition for which a reduction in blood pressure and/or promoting renalblood flow and/or inhibiting or decreasing sodium reabsorption isexpected to be or is beneficial.

Articles of manufacture comprising a compound of the invention, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule and the like.

In one aspect, a compounds detailed herein as provided herein exhibitsthe ability to cross the blood-brain barrier. In another aspect, acompounds detailed herein as provided herein is not able to cross theblood-brain barrier. In one aspect, a compounds detailed herein asprovided herein exerts its therapeutic effect in the brain only. In oneaspect, a compounds detailed herein as provided herein exerts itstherapeutic effect in the periphery only. In one aspect, a compoundsdetailed herein as provided herein exerts its therapeutic effect both inthe brain and peripherally. In some embodiments, the adrenergic receptorα_(2B) antagonist is a selective adrenergic receptor α_(2B) antagonist.In some embodiments, the adrenergic receptor α_(2B) antagonist alsoexhibits adrenergic receptor α_(2A) antagonist and/or inverse agonistactivity.

Blood brain barrier permeability can be measured in rodents or dog byadministering the compound orally or intravenously, recovering a bloodand brain tissue sample at different time points and comparing how muchcompound is in each sample. Blood fraction is typically processed toplasma for determination of compound content. Brain exposure can bedescribed from the ratio of brain to plasma levels of drug. In onevariation, a compound that poorly crosses the blood brain barrier has abrain to plasma ratio of compound of about 0.1 or less. In anothervariation, the compound has a brain to plasma ratio of about 0.2 orless, about 0.3 or less, about 0.4 or less, about 0.5 or less, about 0.8or less, or about 1.0 or less.

Preferably, the compounds detailed herein are orally bioavailable.However, the compounds may also be formulated for parenteral (e.g.,intravenous) administration. In some settings, parenteral administrationof an adrenergic receptor α_(2B) antagonists (e.g., selective adrenergicreceptor α_(2B) antagonist) may be desired. For example, intra-renaldelivery may offer treatment options for acute and chronic renalfailure, end stage renal failure and acute decompensated congestiveheart failure. Parenteral formulation may be preferred in the treatmentof hypertensive urgency and emergency. In some embodiments, theadrenergic receptor α_(2B) antagonist is a selective adrenergic receptorα_(2B) antagonist. In some embodiments, the adrenergic receptor α_(2B)antagonist also exhibits adrenergic receptor α_(2A) antagonist and/orinverse agonist activity.

One or several compounds described herein can be used in the preparationof a medicament by combining the compound or compounds as an activeingredient with a pharmacologically acceptable carrier, which are knownin the art. Depending on the therapeutic form of the medication, thecarrier may be in various forms. In one variation, the manufacture of amedicament is for use in any of the methods disclosed herein, e.g.,reducing the blood pressure of an individual, promoting renal blood flowand/or decreasing or inhibiting sodium reabsorption.

Methods as provided herein may comprise administering to an individual apharmacological composition that contains an effective amount of acompound and a pharmaceutically acceptable carrier. The effective amountof the compound may in one aspect be a dose of between about 0.01 andabout 100 mg.

The compound may be formulated for any available delivery route,including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal orrectal), parenteral (e.g., intramuscular, subcutaneous or intravenous),topical or transdermal delivery form. A compound may be formulated withsuitable carriers to provide delivery forms that include, but are notlimited to, tablets, caplets, capsules (such as hard gelatin capsules orsoft elastic gelatin capsules), cachets, troches, lozenges, gums,dispersions, suppositories, ointments, cataplasms (poultices), pastes,powders, dressings, creams, solutions, patches, aerosols (e.g., nasalspray or inhalers), gels, suspensions (e.g., aqueous or non-aqueousliquid suspensions, oil-in-water emulsions or water-in-oil liquidemulsions), solutions and elixirs.

One or several compounds described herein can be used in the preparationof a formulation, such as a pharmaceutical formulation, by combining thecompound or compounds as an active ingredient with a pharmaceuticallyacceptable carrier, such as those mentioned above. Depending on thetherapeutic form of the system (e.g., transdermal patch vs. oraltablet), the carrier may be in various forms. In addition,pharmaceutical formulations may contain preservatives, solubilizers,stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters,salts for the adjustment of osmotic pressure, buffers, coating agents orantioxidants. Formulations comprising the compound may also containother substances which have valuable therapeutic properties.Pharmaceutical formulations may be prepared by known pharmaceuticalmethods. Suitable formulations can be found, e.g., in Remington'sPharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa.,20^(th) ed. (2000), which is incorporated herein by reference.

Compounds as described herein may be administered to individuals in aform of generally accepted oral compositions, such as tablets, coatedtablets, gel capsules in a hard or in soft shell, emulsions orsuspensions. Examples of carriers, which may be used for the preparationof such compositions, are lactose, corn starch or its derivatives, talc,stearate or its salts, etc. Acceptable carriers for gel capsules withsoft shell are, for instance, plant oils, wax, fats, semisolid andliquid poly-ols, and so on. In addition, pharmaceutical formulations maycontain preservatives, solubilizers, stabilizers, re-wetting agents,emulgators, sweeteners, dyes, adjusters, salts for the adjustment ofosmotic pressure, buffers, coating agents or antioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described, for example, a compound as described hereinor a pharmaceutically acceptable salt thereof can be formulated as a 10mg tablet.

The compound may be administered to an individual in accordance with aneffective dosing regimen for a desired period of time or duration, suchas at least about one month, at least about 2 months, at least about 3months, at least about 6 months, or at least about 12 months or longer,which in some variations may be for the duration of the individual'slife. In one variation, the compound is administered on a daily orintermittent schedule. The compound can be administered to an individualcontinuously (for example, at least once daily) over a period of time.The dosing frequency can also be less than once daily, e.g., about aonce weekly dosing. The dosing frequency can be more than once daily,e.g., twice or three times daily. The dosing frequency can also beintermittent (e.g., once daily dosing for 7 days followed by no dosesfor 7 days, repeated for any 14 day time period, such as about 2 months,about 4 months, about 6 months or more). Any of the dosing frequenciescan employ any of the compounds described herein together with any ofthe dosages described herein.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound and apharmaceutically acceptable carrier or excipient. In another variation,a composition of substantially pure compound is provided.

The invention further provides kits for carrying out the methods of theinvention, which comprises one or more compounds described herein or apharmacological composition comprising a compound described herein. Thekits may employ any of the compounds disclosed herein. In one variation,the kit employs a compound described herein or a pharmaceuticallyacceptable salt thereof. The kits may be used for any one or more of theuses described herein, and, accordingly, may contain instructions forany one or more of the following uses: treating, preventing, and/ordelaying the onset and/or development of hypertension and/or a diseaseor condition which is responsive, or expected to be responsive, to (i) areduction in an individual's blood pressure and/or (ii) an increase inrenal blood flow and/or (iii) a decrease or inhibition of sodiumreabsorption.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present invention. Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

The invention also provides compositions (including pharmacologicalcompositions) as described herein for the use in treating, preventing,and/or delaying the onset and/or development of hypertension and/or adisease or condition which is responsive, or expected to be responsive,to (i) a reduction in an individual's blood pressure and/or (ii) anincrease in renal blood flow and/or (iii) a decrease or inhibition ofsodium reabsorption and other methods described herein.

Representative compounds of the invention are shown in Tables 1-4.

TABLE 1 Representative Compounds of the Invention Compound No. StructureA1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

A73

A74

A75

A76

A77

A78

A79

A80

A81

A82

A83

A84

A85

A86

A87

A88

A89

A90

A91

A92

A93

A94

A95

A96

A97

A98

A99

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

A111

A112

A113

A114

A115

A116

A117

A118

A119

A120

A121

A122

A123

A124

A125

A126

A127

A128

A129

A130

A131

A132

A133

A134

A135

A136

A137

A138

A139

A140

A141

A142

A143

A144

A145

A146

A147

A148

A149

A150

A151

A152

A153

A154

A155

A156

A157

A158

A159

A160

TABLE 2 Representative Compounds of the Invention Com- pound No.Structure B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B52

B53

B54

B55

B56

B57

B58

B59

B60

B61

B62

B63

B64

B65

B66

B67

B68

B69

B70

B71

B72

B73

B74

B75

B76

B77

B78

B79

B80

B81

B82

B83

B84

B85

B86

B87

B88

B89

B90

B91

B92

B93

B94

B95

B96

B97

B98

B99

B100

B101

B102

B103

B104

B105

B106

B107

B108

B109

B110

B111

B112

B113

B114

B115

B116

B117

B118

B119

B120

B121

B122

B123

B124

B125

B126

B127

B128

B129

B130

B131

B132

B133

B134

B135

B136

B137

B138

B139

B140

B141

B142

B143

B144

B145

B146

B147

B148

B149

B150

B151

B152

B153

B154

B155

B156

B157

B158

B159

B160

B161

B162

B163

B164

B165

B166

B167

B168

B169

B170

B171

B172

B173

B174

B175

B176

B177

B178

B179

B180

B181

B182

B183

B184

B185

B186

B187

B188

B189

B190

B191

B192

B193

B194

B195

B196

B197

B198

B199

B200

B201

B202

B203

B204

B205

B206

B207

B208

B209

B210

B211

B212

B213

B214

B215

B216

B217

B218

B219

B220

B221

B222

B223

B224

B225

B226

B227

B228

B229

B230

B231

B232

B233

B234

B235

B236

B237

B238

B239

B240

B241

B242

TABLE 3 Representative Compounds of the Invention Com- pound No.Structure C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

C14

C15

C16

C17

C18

C19

C20

C21

C22

C23

C24

C25

C26

C27

C28

C29

C30

C31

C32

C33

C34

C35

C36

C37

C38

C39

C40

C41

C42

C43

C44

C45

C46

C47

C48

C49

C50

C51

C52

C53

C54

C55

C56

C57

C58

C59

C60

C61

C62

C63

C64

C65

C66

C67

C68

C69

C70

C71

C72

C73

C74

C75

C76

C77

C78

C79

C80

C81

C82

C83

C84

C85

C86

C87

C88

C89

C90

C91

C92

C93

C94

C95

C96

C97

C98

C99

C100

C101

C102

C103

C104

C105

C106

C107

C108

C109

C110

C111

C112

C113

C114

C115

C116

C117

C118

C119

C120

C121

C122

C123

C124

C125

C126

C127

C128

C129

C130

C131

C132

C133

C134

C135

C136

TABLE 4 Representative Compounds of the Invention Com- pound No.Structure D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

D26

D27

D28

D29

D30

D31

D32

D33

D34

D35

D36

D37

D38

D39

D40

D41

D42

D43

D44

D45

D46

D47

D48

D49

D50

D51

D52

D53

D54

D55

D56

D57

D58

D59

D60

D61

D62

D63

D64

D65

D66

D67

D68

D69

D70

D71

D72

D73

D74

D75

D76

D77

D78

D79

D80

D81

D82

D83

D84

D85

D86

D87

D88

D89

D90

D91

D92

D93

D94

D95

D96

D97

D98

D99

D100

D101

D102

D103

D104

D105

D106

D107

D108

D109

D110

D111

D112

D113

D114

D115

D116

D117

D118

D119

D120

D121

D122

D123

D124

D125

D126

D127

D128

D129

D130

D131

D132

D133

D134

D135

D136

D137

D138

D139

D140

D141

D142

D143

D144

D145

D146

D147

D148

D149

D150

D151

D152

D153

D154

D155

D156

D157

D158

D159

D160

D161

D162

D163

D164

D165

D166

D167

D168

D169

D170

D171

D172

D173

D174

D175

D176

D177

D178

D179

D180

D181

D182

D183

D184

D185

D186

D187

D188

D189

D190

D191

D192

D193

D194

D195

D196

D197

D198

D199

D200

D201

D202

D203

D204

D205

D206

D207

D208

D209

D210

D211

D212

D213

D214

D215

D216

D217

D218

D219

D220

D221

D222

D223

D224

D225

D226

D227

D228

D229

D230

D231

D232

D233

D234

D235

D236

D237

D238

D239

D240

D241

D242

D243

D244

D245

D246

D247

D248

D249

D250

D251

D252

D253

D254

D255

D256

D257

D258

D259

D260

D261

D262

D263

D264

D265

D266

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

General Protocol for Chiral Preparative HPLC Separation of RacemicCompounds

For chiral separations, samples were dissolved in Methanol and Ethanolaccording to the solubility of sample and filtered through 0.22μ PTFEfilters. The columns used were CHIRALPAK-AD; 20*250 mm, 10μ andCHIRALCEL-ODH; 20*250 mm, 5μ. A flow rate of 12 mL/min-17 mL/min wasused according to the resolution. Alkanes such as n-Pentane, Hexane andHeptane (40%-95%) and alcohols such as Ethanol, Isopropyl alcohol andt-Butanol (5%-60%) were used as mobile phase. In some cases alcoholcombinations i.e. (Ethanol+Methanol), (Ethanol+IPA), (IPA+Methanol),(t-Butanol+Methanol), (t-Butanol+Ethanol) were used instead of a singlealcohol. Diethyl amine (up to 0.3%) was used as modifier in the mobilephase.

The following abbreviations are used herein: thin layer chromatography(TLC); hour (h); minute (min); second (sec); ethanol (EtOH);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor(Rf); room temperature (RT).

General methods of preparing compounds according to the invention aredepicted in exemplified methods below. Other compounds of the inventionmay be prepared by similar methods. Synthetic methods to provide similarintermediates have also been described in, for example, PCT PublicationNos. WO2009-055828, WO2009-094668, WO2009-120717, WO2009-120720,WO2009-038161, WO2009-038162 and WO2009-038164. Synthetic methods toprovide azepino[4,5-b]indole intermediates have been described in PCTPublication No. WO-2009-051503. Synthetic methods to provide bicyclopyrido[3,4-b]indoles have been described in PCT Publication No.WO2009-038163. The synthesis of Compound Nos. A1 to A160 has beendescribed specifically in PCT Publication No. WO2011-103433. Thesynthesis of Compound Nos. B1 to B242 has been described specifically inPCT Publication No. WO2011-103460. The synthesis of Compound Nos. C1 toC136 has been described specifically in PCT Publication No.WO2011-103487. The synthesis of Compound Nos. D1 to D266 has beendescribed specifically in PCT Publication No. WO2011-103485. Theexperimental details of each of these Applications are incorporatedherein by reference.

Exemplified routes to synthesizing particular compounds of the inventionare shown in the General Methods below.

General Method A1.

Step 1: Preparation of compound 1-B.

A solution of 4-chloro-2-bromophenyl hydrazine hydrochloride (15 g, 58mmol) and 1-methylpiperidin-4-one (6.57 g, 58 mmol) in 7% H₂SO₄ indioxane (150 mL) is stirred at 80° C. for 5 h. The progress of reactionis monitored by TLC. The reaction mixture is concentrated under reducedpressure to dryness. The residue is basified with aq. NaOH solution andextracted with EtOAc. The organic layer is dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude product,which is purified by column chromatography (7% MeOH-DCM) to yieldcompound 1-B (7.6 g).

Step 2: Preparation of compound 1-C.

A stirred solution of6-bromo-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(1-B) (200 mg, 0.667 mmol) in DMF (2 mL) is cooled to −78° C., followedby addition of sodium hydride (20 mg, 0.800 mmol) and methyl iodide (2Min DMF, 0.3 mL, 0.60 mmol). The reaction mixture is stirred at −78° C.for 5 min. Ice-water is added into the reaction mixture and the mixtureis then extracted with EtOAc (2×10 mL). The combined organic layer isdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude material, which is purified by columnchromatography using silica (100:200 mesh) and 0-4%

MeOH:DCM to yield compound 1-C (38 mg).

Step 3: Preparation of compound 1-D.

A mixture of6-bromo-8-chloro-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole(1-C) (210 mg, 0.670 mmol), copper(I)iodide (1.3 mg, 0.007 mmol),dichlorobis(triphenylphosphine) palladium(II) (24 mg, 0.034 mmol) isevacuated and back filled with nitrogen. Triethylamine (2.5 mL) isadded, followed by dropwise addition of ethynyltriisopropylsilane (146mg, 0.804 mmol). The reaction mixture is stirred at 85° C. overnight.Water is added into the reaction mixture and the mixture is thenextracted with EtOAc. The organic layer is dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crudematerial, which is purified by column chromatography using silica(100:200 mesh) and 0-4% MeOH:DCM to yield compound 1-D (218 mg).

Step 4: Preparation of compound 1-E.

To an ice cooled stirred solution of8-chloro-2,3,4,5-tetrahydro-6-(2-(triisopropylsilyl)ethynyl)-2,5-dimethyl-1H-pyrido[4,3-b]indole(1-D) (212 mg, 0.512 mmol) in dry THF (10 mL) is addedtetrabutylammoniumfluoride (1M solution in THF, 1.638 mL, 1.638 mmol).The reaction mixture is allowed to warm to RT and stirring continued for15 min. Water is added into the reaction mixture and the mixture isextracted with EtOAc (2×25 mL). The organic layer is dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford compound 1-E (166 mg).

Step 5: Preparation of compound 1-F.

A mixture of8-chloro-6-ethynyl-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole(1-E) (166 mg, 0.642 mmol), 5-bromo-2-methylpyridine (132 mg, 0.770mmol), dichlorobis(triphenyl phosphine)palladium (II) (23 mg, 0.032mmol) and copper (I) iodide (1.1 mg, 0.006 mmol) is evacuated and backfilled with nitrogen. Triethylamine (2 mL) is added dropwise undernitrogen atmosphere. The reaction mixture is stirred at 85° C.overnight. Triethylamine is evaporated under reduced pressure. Theresidue is dissolved in water (10 mL) and extracted with EtOAc (2×25mL). The organic layer is washed with water (2×10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford crude material, which is purified by column chromatography usingneutral alumina and 0-8% MeOH-EtOAc, followed by reverse phase HPLC toyield compound 1-F as the free base (16.23 mg).

General Method A2.

Step 1: Preparation of compound 2-B.

To a suspension of 2-chlorophenyl hydrazine hydrochloride (2-A) (19.7 g,0.110 mol) in dioxane (190 mL) is dropwise added conc. H₂SO₄ (8 mL,0.150 mol). After stirring for 10 min, N-methyl-4-piperidone (17.53 g,0.154 mol) is added into the reaction mixture and stirring continued atRT for 20 min. The reaction mixture is then stirred at 80° C. for 4 h.The progress of reaction is monitored by TLC. The solvent is removedunder reduced pressure and the pH of the residue adjusted to pH 8-9 byaddition of saturated sodium bicarbonate solution. The aqueous layer isextracted with EtOAc (3×300 mL). The combined organic layer is washedwith water, followed by brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which ispurified by re-crystallization (Ether/Hexane) to yield compound 2-B as abrown solid (7.5 g).

Step 2: Preparation of compound 2-C.

To a degassed mixture of6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2-B) (100mg, 0.5 mmol), sodium tert-butoxide (576 mg, 6.0 mmol), palladiumacetate (22.4 mg, 0.1 mmol) and 2,4di-tert-butylphosphino-2′,4′,6′-triisopropyl biphenyl (63.0 mg, 0.15mmol) is added dry toluene (2 mL). After stirring for 5 min,benzylmethylamine (0.09 mL, 0.7 mmol) is added to the reaction mixture,which is stirred at 100° C. for 16 h. The reaction mixture is filteredand the residue washed with EtOAc. The filtrate is concentrated underreduced pressure to afford crude material, which is purified by reversephase HPLC to yieldbenzyl-methyl-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl)-amine(2-C) (50 mg).

General Method A3.

Alcohol compounds of type 3-C can be prepared from the bromo precursor3-A by treatment with epoxide 3-B under standard Grignard orGrignard-cuprate coupling conditions known to those skilled in the art.Fluorination of 3-C with agents such as Diethylaminosulfur-trifluoride(DAST) provides the fluoro derivative 3-D. Alternatively, treatment of3-A with alkene 3-E under Heck coupling conditions affords the styrylproduct of the type 3-F. Alternative coupling conditions includingStille and Suzuki, and the like, using corresponding reagents, will befamiliar to those skilled in the art.

General Method B1.

Nitrile compound 1-A, if not commercially available, can be synthesizedfrom precursors such as the halo, hydroxyl and/or ester compounds, usingstandard functional group conversion means known to those skilled in theart. Compound 1-A is subjected to a condensation reaction with aldehyde1-B to produce alkene 1-C which is reduced to alkane intermediate 1-D.Hydrogenation of 1-D results in cyclization to the tetrahydroquinoline1-E which, when subjected to nitrosation conditions, yields nitrosocompound 1-F. Reduction of 1-F with zinc dust in the presence of acetoneyields ylide 1-G which when heated with acid in the presence ofpiperidone 1-H, provides the desired final tetracyclic product 1-J.

General Method B2.

Aldehyde 2-A is subjected to Fischer-Indole synthesis conditions withhydrazine 2-B to give indole 2-C. Mild reduction of 2-C results inindoline 2-D. In an analogous fashion to the conversion oftetrahydroquinoline 1-E to tetracyclic compound 1-J, indoline 2-D issubjected to nitrosating conditions to give nitroso intermediate 2-Ewhich, when subjected to zinc dust in the presence of acetone, affordylide 2-F, and thence provides tetracyclic final product 2-H followingtreatment with piperidone 2-G and acid.

General Method B3.

Cyclization of o-hydroxy-aniline 3-A with an appropriately substituteddihaloalkane, such as 1,2-dibromoethane, yields benzoxazine 3-B.Nitrosation yields nitroso intermediate 3-C which, when heated withpiperidone 3-D in acid produces the desired tetracyclic product 3-F.Alternatively, under similar conditions, the o-amino-thiophenol 3-F (or2,2′-disulfanediyldianiline derivative) yields the intermediatebenzothiazine 3-G and thence the thio analog 3-J. Alternatively, undersimilar conditions, the o-amino-aniline 3-K (R″═H, alkyl) yields theintermediate tetrahydroquinoxaline 3-L and thence the amino analog 3-N.

Use of alternative haloacetates, such as ethyl-2-bromoacetate in placeof the dihaloalkanes, results in the acyl analog of the types 3-0 and3-P. Use of α-substituted ethyl-2-bromoacetate reagents yieldssubstituted analogs of the type 3-Q and 3-R. Compounds 3-S and 3-T canbe prepared through reduction of the compounds 3-Q and 3-R, orintermediates thereto, respectively.

An alternative route commences by nucleophilic substitution of theorthohalonitrobenzene compound 3-U with an appropriately substitutednucleophilic alkyl halide 3-V followed by reduction of the nitro groupto the amine 3-W. Conversion to the aryl hydrazine 3-X followed byFischer-Indole reaction with piperidone 3-D as before gives the desiredR′-substituted product 3-Y.

General Method B4.

Conversion of phenyl hydrazine 4-A to the intermediate ylide 4-Bfollowed by cyclization yields the indole 4-C. Reduction of the indole4-C to the indoline 4-D followed by nitrosation yields nitrosoderivative 4-E which, after conversion to the successive ylide 4-F,yields the final tetracyclic product 4-H upon treatment with piperidone4-G.

General Method B5.

Suzuki-coupling of bromoquinoline 5-A with an appropriately substitutedboronic acid yields the aryl-coupled product 5-B. Reduction of 5-B tothe tetrahydroquinoline 5-C followed by nitrosation gives the nitrosointermediate 5-D. Conversion of nitroso compound 5-D to the ylide 5-E,followed by heating with piperidone 5-F yields the final desiredtetracycle 5-G.

General Method B6.

Appropriately substituted aryl hydrazine 6-A is treated with piperidone6-B to produce the carboline tricycle 6-C. Base-mediated N-alkylation of6-C with an appropriately substituted propene derivative results in thesubstituted allyl adduct 6-D. Allylation (n=11) at the bromo-substitutedcenter of 6-D under Stille coupling conditions provides the allylatedproduct 6-E. Finally, conversion to the cyclized tetracyclic azepinoproduct 6-F is achieved under ring-closing metathesis (RCM) conditionsinvolving catalysts known in the art, such as Grubbs “First GenerationCatalyst”, “Second Generation Catalyst”, “Hoveyda-Grubbs Catalyst”, andthe like. Reduction of 6-F under for example, hydrogenation conditionsyields the saturated derivative 6-G. Alternatively, where n=0,vinylation of 6-D provides the vinylated version of 6-E, from which RCMresults in the 6-membered analog of 6-F, with successive reductionproducing saturated product 6-G.

General Method B7.

Treatment of appropriately substituted aryl hydrazine 7-A withpiperidone 7-B results in the tricyclic carboline product 7-C. Palladiummediated amination of 7-C at the chloro-center, under Buchwald-Hartwigconditions, provides the aniline product 7-D. Reaction of 7-D with2-chloroacetylchloride results in the tetracyclic piperazinone-typeproduct 7-E.

General Method B8.

Treatment of appropriately substituted carboline 8-A withmethylmagnesium chloride, followed by diethyl oxalate gave the esterintermediate 8-B which, following successive addition of the Grignardreagent R^(a)MgCl and/or R^(b)MgCl (or alternatively 2 equivalents ofR^(a)MgCl) provides the tertiary alcohol product 8-C. Acid-mediatedcyclization of 8-C affords the tetracyclic amide 8-D, from whichreduction of the amide group under standard reductive conditions yieldsthe amine final product 8-E.

General Method B9.

Treatment of appropriately substituted carboline 9-A with anα,β-unsaturated carbonyl compound such as acid chloride 9-B provides theamide 9-C. Lewis-acid-mediated cyclization of 9-C results in thetetracyclic product 9-D, whereupon reduction of which yields the finalamine 9-E. Alternatively, treatment of 9-A with appropriatelysubstituted acid chloride such as 9-F yields the amide 9-G, followed bycyclization to amide 9-H and reduction to the amine 9-J.

General Method B10.

The appropriately substituted indoline such as that from General Method4,4-D, is converted to the N-carboxyethyl derivative 10-A. Base-mediatedalkylation of 10-A leads to the alkylated product 10-B. Removal of thecarboxymethyl group under basic conditions produces the secondary amine10-C. Further conversion, following conditions analogous to thosedescribed in General Method 4, yields the desired tetracyclic product10-G.

General Methods for the preparation of intermediate compounds to providebicyclic analogs described herein are presented below in General Methods11-13. Such bicyclic intermediates can be subjected to the conditionsdescribed in the Methods presented above.

General Method B11.

An appropriately substituted arylhydrazine 11-A is treated with alkylhalide 11-B to provide the N-alkylated product 11-C. Ring-closure of11-C with acetal 11-D gives the 3-substituted indole 11-E which, uponheating with formaldehyde affords the tetracyclic product 11-F. Theportion comprising R² and R⁴ can be converted to a ring during thisroute, using the Methods described above.

General Method B12.

Suitably substituted indole 12-A is reacted with maleimide 12-B to give3-substituted derivative 12-C, followed by reduction with an appropriatereducing agent to generate substituted 3-(3-pyrrolidinyl)indole 12-D.This 3-(3-pyrrolidinyl)indole 12-D can then be reacted withformaldehyde, under standard Pictet Spingler reaction conditions (U.S.Pat. No. 2,642,438) to give the bicyclo-β-carboline 12-E. Thisβ-carboline can then be functionalized to give cyclic product 12-F in ananalogous manner to those steps provided for in the other GeneralMethods described above.

General Method B13.

General Method 13 includes the use of Fischer-Indole conditions, wellknown to those in the art, whereby an appropriately substituted arylhydrazine 13-A is condensed with various ketones, as exemplified by13-B-13-D, to form aryl hydrazones, which are heated in dilute acid tocomplete the cyclization and provide the carboline products 13-E-13-G,respectively. If necessary any isomers can be separated at this stage,or after later steps. The carbolines can then be substituted at the NHposition and/or at R⁴ using the conditions described in the GeneralMethods above. The synthesis of the bicyclic ketone intermediates hasbeen described by Bastable et al. [J. Chem. Soc. Perkin I (1981),1346-1351]; King et al. [J. Med. Chem. (1993), 36:683-689]; and Mewshawet al. [J. Med. Chem. (1993), 36:343-352], the experimental detailstherein are hereby incorporated by reference.

General Method B14 Preparation of N-Methyl and N-Ethyl9-Chloro-1,2,3,4,5,6-hexhydroazepino[4,3-b]indole

A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol),1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acidmonohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h.The reaction was cooled and EtOAc (50 mL) was added and the organicphase was washed with water (20 mL) and brine (20 mL), dried over sodiumsulfate, filtered and evaporated to give a brown solid, which waspurified by column chromatography [Silica, eluent: EtOAc:hexane to give3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55g, 80%).

A mixture of 3-(4-chloro-2-iodo-phenylamino)-cyclohex-2-enone (0.5 g,1.44 mmol), cuprous iodide (27.4 mg, 0.14 mmol), L-proline (33.12 mg,0.29 mmol) and potassium hydroxide (0.32 g, 5.70 mmol) in DMSO (6 mL)were heated to 90° C. for 24 h. The reaction was cooled and poured intowater. The aqueous phase was extracted with EtOAc (3×50 mL). Thecombined organic phase was washed with brine (25 mL), dried overmagnesium sulfate, filtered and the solvent removed under reducedpressure to give a dark brown solid. This was recrystallized usingacetonitrile water to give a brown solid (0.17 g, 54%). mp 281-282° C.

A solution of 6-chloro-2,3-dihydro-1H-carbazol-4(9H)-one (500 mg, 2.27mmol), hydroxylamine hydrochloride (238 mg, 3.41 mmol) and NaOAc (280mg, 3.41 mmol) in EtOH:water (4.5:2 mL) was heated to reflux (125° C.)for 5 h. The reaction mixture was concentrated to dryness. Water wasadded to the residue and the solid filtered, dried under vacuum to yieldthe title compound.

6-Chloro-2,3-dihydro-1H-carbazol-4(9H)-one oxime (4.39 g, 18.71 mMol)and polyphosphoric acid (119 g) was heated together at 120° C. for 20min. After cooling to RT, ice-water mixture was added to hydrolyze themixture and stirred for 2 h. The mixture was filtered and washed withNH₄OH (40 ml) followed by water. The resultant solid was dissolved inMeOH and filtered. The methanolic solution was concentrated to yield 4.7g of crude as a brown solid. The crude product was purified by flashcolumn chromatography over silica-gel (230-400 mesh) using EtOAc/Hexanefollowed by MeOH/EtOAc, the product eluting at 2-10% MeOH/EA.

Yield: 2.1 g (47.8%).

To an ice-cooled stirred suspension of Lithiumaluminum hydride (486 mg,12.8 mmol) in dry THF (29 mL) was added dropwise a solution of9-chloro-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (380 mg, 1.62mmol) in dry THF (20 mL), and the reaction mixture heated to reflux for15 h (89° C.). The reaction mixture was cooled to RT, quenched withwater (3 mL), and 15% NaOH solution (6 mL) and water (9 mL), and thendiluted with THF. The reaction mixture was filtered through Celite andthe filtrate concentrated under reduced pressure to yield the titlecompound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360mg, 1.6 mmol) in THF (1 mL) was added dropwise to ethyl formate (1 mL).The reaction mixture was stirred at RT for 30 min, followed by heatingto reflux for 14 h. The solvent was removed under reduced pressure toyield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360mg, 1.6 mmol) was stirred in acetic anhydride for 12 h. The solvent wasremoved under reduced pressure to yield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (12.3g, 55.9 mmol) in ethylformate (369 mL) was stirred at 55° C. for 2 h.The progress of reaction was monitored by TLC. The reaction mixture wasconcentrated under reduced pressure and the crude product (13.5 g) wasused for the next step without purification. To a stirred suspension oflithiumaluminum hydride (4.13 g, 108.8 mmol) in dry THF (405 mL) wasadded portionwise9-chloro-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (13.5g) and the mixture heated to reflux for 2 h. The progress of reactionwas monitored by TLC. The reaction was quenched with saturated aqueoussodium sulfate solution at 0° C., and the mixture filtered. The filtratewas dried over anhydrous sodium sulfate and evaporated to dryness. Theresidue was washed with diethyl ether to yield the title compound (9.7g). ¹H NMR (DMSO) δ (ppm): 11.02 (s, 1H, D₂O exchangeable), 7.45 (s,1H), 7.25-7.22 (d, 1H), 6.98-6.95 (d, 1H), 3.72 (s, 2H), 2.90-2.80 (m,4H), 2.30 (s, 3H), 1.82-1.77 (m, 2H).

To an ice-cooled stirred suspension of lithiumaluminum hydride (390 mg,10.09 mmol) in 1,4-dioxane (15 mL) was added portionwise1-(9-chloro-4,5-dihydroazepino[4,3-b]indol-2(1H,3H,6H)-yl)ethanone (300mg, 1.14 mmol), and the reaction mixture heated to reflux for 6 h. Thereaction mixture was quenched with water (1 mL), 15% aq. NaOH solution(3 mL) and water (3 mL), and extracted with warm EtOAc (3×50 mL). Thecombined organic extract was concentrated and the residue purified bysilica gel (230-400 mesh) flash column chromatography (100% EtOAc) toyield the title compound (115 mg).

General Method B15 Preparation of2,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole

To a solution of p-tolylhydrazine hydrochloride (7.5 g, 47.2 mmol) in1,4-dioxane:conc. H₂SO₄ (225:16.5 mL) was added cyclohexane-1,3-dione(4.42 g, 39.4 mmol), and the mixture heated to reflux for 16 h (85-90°C.). The reaction mixture was cooled to RT, basified with 15% aqueousKOH (pH 10) and extracted with EtOAc. The organic layer was washed twicewith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to yield the title compound (7.7 g, crude).

A solution of 2,3-dihydro-6-methyl-1H-carbazol-4(9H)-one (5.8 g, 19.1mmol), hydroxylamine hydrochloride (3.0 g, 43.6 mmol) and NaOAc (3.58 g,43.6 mmol) in EtOH:water (58:25.3 mL) was heated to reflux (125° C.) for5 h. The reaction mixture was concentrated to dryness. Water was addedto the residue and the solid filtered, dried under vacuum to yield titlecompound.

To a preheated (105° C.) solution of polyphosphoric acid (225 g) wasadded powdered 6-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime (10 g)under nitrogen and heating continued for 15 min. The reaction mixturewas cooled and to it was added crushed ice water. The crystallized solidobtained was collected by filtration. The solid was washed with waterand then by dilute ammonium hydroxide, then dried under vacuum to obtainthe desired product (8 g, crude product).

Lithiumaluminum hydride (3 g, 78.95 mmol) was placed in 1,4-dioxane (100mL) under inert atmosphere and9-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (3 g, 14.018mmol) was added, and the mixture heated to reflux for 15 h. The reactionwas monitored by TLC. The reaction was quenched with saturated aqueoussodium sulfate at 0° C., and the reaction mixture filtered. The filtratewas dried over anhydrous sodium sulfate and evaporated to dryness toafford solid, which was washed with water followed by EtOAc, and driedto afford 1.25 g of the title compound.

9-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (0.25 g, 1.25 mmol)was taken in ethylformate (18 mL, 227 mmol) and stirred at 55° C. for 3h. The reaction was monitored by TLC. The reaction mixture wasevaporated under reduced pressure and used for the next step withoutpurification (0.2 g).

To a stirred suspension of lithiumaluminum hydride (2 g, 52.63 mmol) indry THF (150 mL) was added portionwise9-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (5.9g, 25.87 mmol) and the reaction mixture stirred at 55° C. for 2 h. Theprogress of reaction was monitored by TLC. The reaction mixture wasquenched with saturated sodium aqueous sulfate solution at 0° C. andthen filtered. The filtrate was dried over anhydrous sodium sulfate andevaporated to dryness to afford the title compound (5.2 g). ¹H NMR(DMSO) 6 (ppm): 7.12-7.05 (m, 2H), 6.80-6.6.76 (d, 1H), 3.65 (s, 2H),2.90-2.80 (m, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.80-1.72 (m, 2H).

General Method C1

Treatment of appropriately substituted dimethylpiperidone 1-A with basessuch as sodium hydride followed by addition of electrophile 1-B providesthe alkylated product 1-C which, after heating with appropriatelysubstituted hydrazine 1-D in the presence of acid provides the cyclizedcarboline product 1-E.

General Method C2

Treatment of appropriately substituted hydrazine 2-A with base andelectrophile 2-B yields alkylated hydrazine product 2-C which, afterheating with acid and appropriately substituted piperidone 2-D providesthe cyclized carboline product 2-E.

General Method C3

Substituted piperidones of the type exemplified as compound 2-D inGeneral Method 2 can be prepared through a number of means known tothose skilled in the art. Common utilized conditions comprise abase-mediated treatment of compound 3-A with an electrophile such as R—Xto produce the α-substituted product 3-B, which would be utilized asdescribed in General Methods 1 and 2 to prepare compounds of the type3-C. R can also be aromatic, wherein conditions can comprisepalladium-mediated coupling reagents. Alternative electrophiles couldinclude, for example, aldehydes, esters, carbonates, anhydrides, and thelike.

Compounds of formulae (A1)-(A4), (A1a-A1r), (A3a)-(A3h), and variationsthereof, are exemplified in Table 1 as compounds A1-A160. Compounds offormulae (B1)-(B4), (B1a)-(B1bm), (B3a-B3d), and variations thereof, areexemplified in Table 2 as compounds B1-B242. Compounds of formulae(C1)-(C4), (C1-a)-(C1r), (C3a)-(C3h), and variations thereof, areexemplified in Table 3 as compounds C1-C136. Compounds of formulae(D1)-(D4), (D1a)-(D1bm), (D3a)-(D3d), and variations thereof, areexemplified in Table 4 as compounds D1-D266.

The following Examples are provided to illustrate but not to limit theinvention.

EXAMPLES Example B1 Determination of the Ability of Compounds of theInvention to Bind an Adrenergic Receptor Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO) K1 cells (Uhlen, S. et al, Eur. J.Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA) was used.Compounds of the invention were incubated with 2.5 nM [3H]Rauwolscinefor 60 min at 25° C. Non-specific binding was estimated in the presenceof 10 μM Prazosin. Receptor proteins were filtered and washed, thefilters were then counted to determine [3H]Rauwolscine specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Compounds of the invention were tested in this biochemicalassay and percent inhibition of specific binding was determined.Biochemical assay results are presented as the percent inhibition ofspecific binding in Tables B1A-B1D.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271:1558,1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1nM [³H]MK-912 for 60 min at 25° C. MK912 was(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds ofthe invention were tested in this biochemical assay and percentinhibition of specific binding was determined. Biochemical assay resultsare presented as the percent inhibition of specific binding in TablesB1A-B1D.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. et al, Biochem. Biophys. Res. Commun. 186:760,1992; Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modifiedTris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.Compounds of the invention were incubated with 0.25 nM [³H]Prazosin for60 min at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prazosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention were tested in this biochemical assay andpercent inhibition of specific binding was determined. Biochemical assayresults are presented as the percent inhibition of specific binding inTables B1A-B1D.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. et al, Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds were incubated with 0.6 nM [3H]Prazosin for 60 min at25° C. Non-specific binding was estimated in the presence of 10 μMphentolamine. Receptor proteins were filtered and washed, the filterswere then counted to determine [3H]Prazosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Tables B1A-B1D.

TABLE B1A Percentage inhibition of ligand binding to aminergic Gprotein- coupled receptors by compounds of the invention: AdrenergicCompound Adrenergic (0.1 μM) (0.03 μM) No. α_(1B) α_(2A) α_(2B) α_(1D)α_(2B) A7 2 10 −9 4 — A8 −3 20 −1 3 — A9 −9 0 −7 −1 — A10 11 23 8 26 —A11 −1 4 14 −1 — A12 2 −4 6 38 — A13 −9 −12 5 8 — A14 0 12 −3 −9 — A15 020 21 5 — A16 1 31 17 −2 — A17 9 14 21 −5 — A18 30 6 38 34 — A43 −1 7 —— 26 A44 −3 −5 — — 31

TABLE B1B Percentage inhibition of ligand binding to aminergic Gprotein-coupled receptors by compounds of the invention: AdrenergicCompound (1 μM) Adrenergic (0.1 μM) No. α_(1D) α_(2A) α_(2B) α_(1B)α_(2A) α_(2B) α_(1D) B1 28 15 47 — — — — B2 24 89 74 — — — — B3 38 89 68— — — — B12 — — 28 75 72 28 B160 — — 2 −1 −8 15 B161 — — 2 13 7 1 B162 —— −6 14 27 −2 B163 — — 6 5 4 15 B164 — — 12 6 16 2 B165 — — 0 40 43 0B210 — — — — 14 — B211 — — — — 82 —

TABLE B1C Percentage inhibition of ligand binding to aminergic Gprotein- coupled receptors by compounds of the invention: Adrenergic(0.1 μM) Compound No. α_(1B) α_(2A) α_(2B) α_(1D) C47 34 15 32 10 C48 202 −12 13

TABLE B1D Percentage inhibition of ligand binding to aminergic Gprotein- coupled receptors by compounds of the invention: Adrenergic(0.1 μM) Compound No. α_(1B) α_(2A) α_(2B) α_(1D) D10 −3 −1 −6 −6 D11 168 30 −5 D12 10 5 −7 −3

Example B2 Functional Activity on Recombinant Adrenergic α_(1B),Adrenergic α_(2A) Adrenergic α_(2B) and Adrenergic α_(1D) ReceptorsUsing Aequorin and GTPγS Functional Assays

To study the functional activity of compounds of the invention on thehuman recombinant adrenergic α_(2B), adrenergic α_(2A), adrenergicα_(1B) or adrenergic α_(1D) with Aequorin functional assays and on thehuman recombinant adrenergic α_(2B) receptor with GTPγS assay, CHO-K1cell lines expressing adrenergic α_(2B), adrenergic α_(2A), adrenergicα_(1B) or adrenergic α_(1D) recombinant receptor, mitochondrialapoaequorin and Gα16 are used for the Aequorin assay. CHO-K1 cell lineexpressing the recombinant α_(2B) receptor is amplified to preparemembranes used for the GTPγS assay.

The following reference agonists are used as both the reference ligandin agonist mode and as the agonist that needs to be inhibited inantagonist mode.

α_(2B) Assay α_(1B) (aeq) α_(1D) (aeq) α_(2A) (aeq) α_(2B) (aeq) (GTPgS)Agonist Cirazoline Cirazoline UK 14304 Oxyme- Guanfacine ligand tazoline

Aequorin Assay Procedure:

Aequorin adrenergic α_(1B) (FAST-008A), adrenergic α_(2A) (FAST-006A) oradrenergic α_(2B) (FAST-007A) cells are grown 18 h prior to the test inmedia without antibiotics. They are then detached by gentle flushingwith PBS-EDTA (5 mM EDTA), recovered by centrifugation and re-suspendedin “assay buffer” (DMEM/HAM's F12 with HEPES+0.1% BSA protease free).Cells are incubated at RT for at least 4 h with Coelenterazine h(Molecular Probes). Dose response curves with reference compounds areperformed before testing the compounds of the invention. The α_(1B)reference agonist and antagonist are cirazoline and qinazoline,respectively. The α_(2A) reference agonist and antagonist are UK14,304and rauwolscine, respectively. The α_(2B) reference agonist andantagonist are oxymetazoline and rauwolscine, respectively.

For agonist testing, 50 μL of cell suspension are injected on 50 μL oftest compound or reference agonist plated in a 96-well plate. Theresulting emission of light is recorded using the Hamamatsu FunctionalDrug Screening System 6000 (FDSS 6000). For antagonist testing,following an incubation of 15 min. after the first injection, 100 μL ofreference agonist at a concentration corresponding to its EC₈₀ isinjected on the 100 μL of the mixture of cell suspension and testcompound. The resulting emission of light is recorded using the sameluminometer as for agonist testing. To standardize the emission ofrecorded light (determination of the “100% signal”) across plates andacross different experiments, some of the wells contained 100 μMdigitonin or a saturating concentration of ATP (20 μM). Plates alsocontained the reference agonist at a concentration equivalent to theEC₈₀ obtained during the test validation.

Agonist activity of test compound is expressed as a percentage of theactivity of the reference agonist at its EC₁₀₀ concentration. Antagonistactivity of test compound is expressed as a percentage of the inhibitionof reference agonist activity at its EC₈₀ concentration.

Test compounds are tested for agonist & antagonist activity at the humanadrenergic α_(1B) (FAST-008A), adrenergic α_(2A) (FAST-006A) oradrenergic α_(2B) (FAST-007A) at the following nanomolar concentrations,in duplicate: Agonist (nM): 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000,10000; Antagonist (nM): 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500, 5000.

GTPγS Assay Procedure:

The procedure is carried out with the following: assay buffer [20 mMHEPES pH 7.4; 100 mM NaCl, 10 μg/mL saponin, 1 mM MgCl₂]; membranes[Recombinant CHO-K1-adrenergic α_(2B) membrane extracts thawed on iceand diluted in assay buffer to give 10 μg/well and kept on ice]; GDP[diluted in assay buffer to give 3 M final concentration]; beads[PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 0.5 mg/well];GTPγ³⁵S [(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nMfinal concentration]; ligand [Guanfacine (Tocris, 1030) as referenceagonist and Rauwolscine (Tocris, 891) as reference antagonist, dilutedin assay buffer]. Membranes are mixed with GDP (volume:volume) andincubated for at least 15 min. on ice. In parallel, GTPγ[³⁵S] is mixedwith the beads (volume:volume) just before starting the reaction.

For agonist testing, the following reagents are successively added inthe wells of an Optiplate (Perkin Elmer): 50 μL of test or referenceligand, 20 μL of the membranes:GDP mix, 10 μL of assay buffer and 20 μLof the GTPγ[³⁵S]:beads mix. For antagonist testing, the followingreagents are successively added in the wells of an Optiplate (PerkinElmer): 50 μL of test or reference ligand, 20 μL of the membranes:GDPmix, and then after an incubation of 15 min. at RT, 10 μL of referenceligand at historical EC₈₀ concentration and 20 L of the GTPγ[³⁵S]:beadsmix.

The plates are covered with a top seal, mixed on an orbital shaker for 2min, and then incubated for 1 h at RT. Then the plates are centrifugedfor 10 min. at 2000 rpm, incubated at RT 4 h and counted for 1 min/wellwith a Perkin Elmer TopCount reader.

Test compounds are tested for antagonist activity at the humanadrenergic α_(2B) receptor (FAST-007G) (FIG. 4) at the followingnanomolar concentrations, in duplicate: Agonist and antagonist (nM):0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000.

Inverse Agonist Activity

SPA 35S-GTPgS and Radioligand Binding experiments are conducted withEuroscreen membrane preparations. Test compound is tested for inverseagonist activity at the human Adrenergic a2A receptor using GTPg35Sbinding functional assay (FAST-006G) in dose-response and in duplicates.

Example B3 Cell Culture and Cell Viability Assay

SH-SY5Y cells cultured in DMEM/F12 media supplemented with 10% FBS wereseeded in 96-well microplates at 150,000 cells/cm². After 24 h, cellswere depleted from FBS and kept in culture for 24 h before theexperiment. A stock solution was prepared by dissolving the calciumionophore 4-Br-A23187 (Calbiochem Cat. N^(o) 100107) in DMSO at 25 mM.Cells were then treated with 4-Br-A23187 (2 μM), hydrogen peroxide (300μM) or the mitochondrial toxin rotenone (25 μM) in the presence ofvehicle or Compound of the Invention for 24 h. Cell death was determinedby measurements of LDH release according to the Cytotoxicity DetectionKitPlus (Roche, Mannheim, Germany). Cell viability was determined bymeasuring the capacity of cells to metabolize MTS tetrazolium (MTS)according to the Cytotoxicity Detection KitPlus (Roche, Mannheim,Germany) and MTS reduction was assessed by the CellTiter 96® AQueous OneSolution Cell Proliferation assay (Promega Corporation, Madison, Wis.,USA). Compounds were screened at 10 nM, using DMSO as vehicle. Assayresults for the experiments with Br-A23187 were presented as the MTSreduction capacity (cell viability) of untreated cells (control),4-Br-A23187-treated cells (vehicle), and co-incubation of Br-A23187 withCompounds of the Invention treated cells and usingp-trifluoromethoxyphenylhydrazone (FCCP) at 10 μM for 30 min as acontrol. This assay assesses the ability of the test compounds toprotect against cell death that was mediated by mitochondrialdysfunction. In the assay, the calcium ionophore 4-Br-A23187 was used tochallenge the cells, causing calcium levels to rise in mitochondria,which leads to depolarization and cell death. Test compounds wereassessed for their ability to prevent cell death in response tochallenge with 4-Br-A23187.

TABLE B3 Relative Cytoprotection efficiency of compounds of theinvention Relative Cytoprotective Compound No. capacity SE p valueControl 100 1.47E−06 — Vehicle 0 0 — A1 −1.10264 48.94656 ns A2 −4.406830.13848 ns A3 35.08263 11.90545 ns A5 28.81883 6.21819 0.0435 A627.59688 3.322046 0.0142 A9 15.84906 12.76087 ns A11 37.63225 18.00517ns A12 35.74884 18.90774 ns A13 19.74211 12.6988 ns A17 10.7958 19.56162ns A18 26.00401 19.9292 ns C43 9.618124 27.03942 ns C44 −0.6341627.95942 ns C45 4.347974 27.88415 ns C46 −0.04527 28.24442 ns C4852.14072 23.16085 ns D2 38.36419 24.02967 ns D5 72.11077 1.5249164.00E−04 D7 72.05842 8.628121 0.014  D8 73.11748 10.89231 0.0215 D981.05257 2.423629 9.00E−04 D11 30.32596 2.105927 0.0048 D12 32.5164714.49203 ns

Example B4 Cell Culture and Cell Viability Assay

Cell Culture.

SH-SY5Y cells stably transfected with a doxycyline (dox)-induciblewild-type α-synuclein (α-syn) gene along with control SH-SY5Y cellsover-expressing the β-galactosidase (β-gal) gene (a gift from L.Stefanis, Division of Basic Neurosciences, Biomedical ResearchFoundation of the Academy of Athens, Athens, Greece) are cultured asdescribed by Vekrellis et al. (Vekrellis K, Xilouri M, Emmanouilidou E,Stefanis L. (2009). Inducible over-expression of α-syn in human neuronalcells leads to caspase-dependent non-apoptotic death. J Neurochem 109,1348-1362). In accordance with this method, cells are cultured andmaintained in RPMI 1640, 10% fetal bovine serum supplemented with 250μg/mL G418 and 50 μg/mL Hygromycin B. Expression of α-syn is switchedoff in stock cultures with doxycycline (2 μg/mL). For experimentalprocedures, cells are plated at (4-8×10⁴ cells/cm²) and differentiatedin absence of doxycycline and in the presence of 20 μM all-transretinoic acid (RA) (Sigma, St Louis, Mo., USA).

Viability Assay:

Cells are cultured in 96-well plates. After 24 h, cells are treated withRA and Compounds of Invention at 0.1 and 10 nM in the absence ofdoxycyline. Culture medium with RA and drugs is fully replaced after 7days. Cell viability is measured by the release of lactate dehydrogenase(LDH) from necrotic cells into the culture medium and by measuring thecapacity of cells to metabolize MTS tetrazolium (MTS) after 14 days inculture. LDH leakage is assessed according to the Cytotoxicity DetectionKitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by theCellTiter 96® AQueous One Solution Cell Proliferation assay (PromegaCorporation, Madison, Wis., USA).

Assay results for the experiments with α-syn over-expression arepresented as the MTS reduction capacity (cell viability) of controlcells (+dox), cells over-expressing α-syn (-dox), and cellsover-expressing α-syn incubated with Compounds of the Invention at 0.1nM or 10 nM.

Immunoblotting of α-Synuclein and α-Synuclein Aggregates:

Cells stably expressing α-synuclein are cultured in 6-well plates at adensity of 4×10⁴ cells/cm² cells per well. Cells are differentiated andtreated with Compound of the Invention at 10 nM in absence of dox after24 h of plating. Drug treatments are repeated after 7 days in freshlyprepared medium containing RA. After 14 days, cells are washed twicewith cold PBS and lysed in lysis buffer containing 1% Triton X-100, 20mM HEPES, 150 mM NaCl, 10% glycerol, 1 mM EGTA, 1.5 mM MgCl₂, 1 mM PMSFpH 7.4, and 1× protease inhibitor mixture (Roche, Mannheim, Germany).Lysates are homogenized and subjected to four successive freeze-thawcycles to disrupt membranes. Triton soluble fractions and tritoninsoluble pellets are obtained by ultracentrifugation at 100,000×g for30 min at 4° C. The concentration of protein in each fraction isdetermined by BCA assay (Thermo Scientific). Samples from total, solubleand triton insoluble fractions, are boiled in 1× sample buffer (20 mMTris, 1% glycerol, 180 mM (3-mercaptoethanol, 0.003% bromophenol blue,and 2% SDS, pH 6.8), loaded on 12% SDS-PAGE gels, and transferred topolyvinylidene difluoride (PVDF) membranes (0.2 μM-pore immobilonBiorad). Membranes are blocked in 1×TBS-Tween (20 mM Tris, pH 7.4, 150mM NaCl, and 0.2% Tween 20) containing 5% milk for 1 h and incubatedovernight at 4° C. with the following primary antibodies in blockingsolution at the indicated dilutions: monoclonal anti-α-synuclein α-syn-1(1:1000; BD Transduction Laboratories). (Perrin, R. J., Payton, J. E.,Barnett, D. H., Wraight, C. L., Woods, W. S., Ye, L., and George, J. M.(2003). Epitope mapping and specificity of the anti-α-synucleinmonoclonal antibody Syn-1 in mouse brain and cultured cell lines.Neurosci Lett 349, 133-135), and monoclonal vimentin (1:1000; BDPharMingen). Primary antibodies are detected with secondary anti-mouseantibodies conjugated to HRP (1:5000).

Isolation of RNA and RT-Quantitative PCR(RT-qPCR):

SH-SY5Y cells stably over-expressing α-syn are treated with Compound ofthe Invention (10 nM). Total RNA from these cells as well as controlcells not treated with Compound is extracted using the E.Z.N.A RNAextraction Kit (OMEGAbiotek, Norcross, Ga.). 1 μg of RNA is reversetranscribed to cDNA using the M-Mulv reverse transcriptase enzyme(Promega Corporation, Madison, Wis., USA). RT-qPCR of cDNA templates iscarried out using TAQMAN probes for human α-synuclein (Hs00240906_M1)and TAQMAN masterMix (Applied Biosystems) and a Mx3005P real-time PCRsystem (Agilent Technologies Inc., Santa Clara, Calif.). Levels ofalpha-tubulin mRNA are used to normalize the amounts of total RNAbetween samples. Fold changes are calculated as described by (Pfaffl, M.W. (2001). A new mathematical model for relative quantification inreal-time RT-PCR. Nucleic Acids Res 29, e45).

Example B5 α_(2B) Pharmacology: Studies in Spontaneously HypertensiveRat (SHR) Model of Hypertension

Male spontaneously hypertensive rats (SHR), approximately 3 months ofage and weighting approximately 250 grams are utilized. Free access tostandard lab chow for rats and reverse osmosis (RO) water is granted.All aspects of this work, including housing, experimentation anddisposal of animals are performed in general accordance with the Guidefor the Care and Use of Laboratory Animals (National Academy Press,Washington, D.C., 1996).

The animals are anaesthetized with sodium pentobarbital (50 mg/kg IP).The left carotid artery when compound dosed orally (PO) orsubcutaneously (SC); and both left carotid and femoral artery whencompound dosed intravenous (i.v.) are cannulated with a polyethylenecatheter (38 cm in length; PE60, Portex, Ltd.) connected with apolyurethane tubing (12 cm in length; PU-40, Cat. #BB520-40, ScientificCommodities, Inc.), which is tunneled under the skin and exited throughthe nape of the neck. The arterial cannula is connected to a pressuretransducer through a swivel system, allowing free roaming duringcontinuous recording of mean arterial pressure and heart rate. Theanimals are housed individually with food and water freely availableduring recovery. On the following day, the arterial cannula is connectedvia a Statham (P 23×L) pressure transducer to a NEC/San-Ei amplifier anddata acquisition and analysis system (Power Lab 8/SP) for direct meanarterial pressure and heart rate measurements.

The test compounds, dissolved in sterile saline, are administeredsubcutaneously (SC) or orally (PO), or by intravenous (i.v.) bolusadministration in two minutes or the escalating doses of compoundadministration in every 30 minutes, with each dose and its strengthdelivered over 2 minutes as shown in the respective figures; theinternal standard phentolamine is given by oral gavage. The controlgroup received vehicle alone. Immediately before (−10 min and −5 min)and at 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 3.5 hr, and 4hr post-dosing, systolic pressure blood pressure values are recorded.Effect of the test compounds on blood pressure is determined.

Example B6 α_(2B) Pharmacology: Studies in Healthy Dogs andDexmedetomidine (DEX) Induced Beagle Dog Model of Hypertension

These studies are conducted in both acute and chronic modes.

Four adult beagle dogs of both sex and weighted around 10 kg are chosenfor the acute studies after a preliminary qualitativeelectrocardiogram/ECG, clinical pathology and physical examination. Uponarrival at the laboratory, the dogs are weighed and acclimated for aperiod of one week. Lab Diet certified canine diet #5007, PMI NutritionInternational Inc is made available ad libitum to all dogs except duringfasting periods. The dogs are surgically implanted with a pressuretransducer equipped telemetry transmitter under sodium pentobarbitoneanesthesia. The transmitter assembly is secured internally and thefluid-filled catheter is placed into an appropriate artery.

In the acute studies, the test compounds at different doses isadministered by oral gavage, 30 minutes prior to intravenousdexmedetomidine (5 μg/kg) challenge. Dexmedetomidine administration isenabled by prior placement of a peripheral intravenous line. The samefour dogs are received all four treatments in the order noted in thetable below, with at least a 3-day washout period between treatments.

In another acute study, the test agent is administered a dose of 6 mg/kgby oral gavage to 4 healthy dogs; and the blood pressure monitored for aperiod of 4 hours.

For the chronic study mode (see Table B9), the test compound at 3 dosesis administered by oral gavage once on day 1 and then twice/day on days2 to 14, and finally once on day 15. The dexmedetomidine is administeredon day −4 to check its effectiveness in inducing blood pressure, andonce following the morning dose of test compound or vehicle on days 2, 7and 14. Blood pressure and heart rate data are collected 1 h prior & 4 hpost-morning dose on days 1, 2, 7, 14 and 15 to allow the appropriatedata comparisons. Blood aliquots are saved at 4 h post-morning dose forexposure determination.

TABLE B9 Chronic dosing sequence and study design for test compound Testcompound - 30 minute Pretreatment (mg/kg, p.o.) with DexmedetomidineNumber of b.i.d. regimen for 14 days Challenge (μg/kg, i.v.) Dogs 0 5 66 5 6 18 5 6 Day −4 1 2 7 14 15 Compound — am am/pm from day 2 to day 14Am dosed on am/pm am/pm DEX* Am — Am am Am — *DEX administered 30 minfollowing am dose of test compound.

In both acute and chronic studies, dogs are weighed before dosing.Cardiovascular evaluations at each dose of test compound are collectedwith animals gently restrained in a sling. Dogs are placed in the slingat least 1 hour prior to dose administration, and after at least 30minutes of stable baseline data collection. The dogs are monitoredcontinuously for 3-4 hours subsequent to test compound administrationand summarized in 5-minute bins. The systolic blood pressure iscollected. Data is reported as mean±SEM or mean.

In acute studies, oral administration of test compound dose-dependentlyreduced systolic blood pressure in both healthy and dexmedetomidineinduced dogs that are tested in the acute mode.

Adrenergic receptors α_(2B) and α_(2A) mixed inhibitor'spharmacology—Studies in Spontaneously Hypertensive Rat (SHR) Model ofHypertension: Similar to dosing regimen for selective antagonists ofadrenergic receptor α_(2B), the mixed inhibitors is dosed orally (PO) orintravenous (i.v bolus or escalating doses) to SHR rats. A compound thatis an adrenergic receptor α_(2B) antagonist also showing adrenergicreceptor α_(2A) antagonist and/or inverse agonist activity can be usefulfor reducing blood pressure in an individual with hypertension who isalso suffering from metabolic syndrome.

Example B7 Peripheral and Central Effects of Test Compound on BloodPressure in Conscious Rabbits

Four adult New Zealand White rabbits of both sexes are chosen for thesestudies. The experiments are conducted in accordance with the Australiancode of Practice for the Care and use of Animals for Scientific Purposesand approval is sought from the Animal Experimental Committee of AlfredHospital, Baker IDI, Melbourne, Australia. The conscious rabbits areimplanted with an intravenous catheter in marginal ear vein or bycentrally by intracisternal catheter interfaced to a pressure transducerconnected to a suitable recorder. To unveil peripheral effects of testcompound, two sets of acute studies are conducted in rabbits. In thefirst set of studies, test compound is dosed to rabbit intravenously fora dose-response study with cumulative doses starting 0 (Ringer's Locksolution as a vehicle), 0.1, 0.3, 1, 3.2 and 10 mg/kg where each dose istested on a separate day. A single intravenous bolus dose at 3 mg/kg isgiven and a time-course study is conducted in the second set of studies.Systolic, diastolic, mean and diastolic blood pressures are recorded inboth the studies. Data collections are made for 3 hours in the secondset of studies. Heart rate (HR) is derived electronically using analgorithm to determine HR from pulse interval. In a separate set ofstudies, Clonidine (positive control) is tested where all experimentalprocedures including dose-regimen are identical to that of the studieswith test compound.

The mean arterial pressure responses to test compound are dose-dependentin the dose-response study with cumulative doses Under similarconditions, Clonidine produces a maximum drop of arterial blood pressureof −6 mmHg before the blood pressure reversed back.

The cardiovascular effects of intracranial administration of testcompound are tested in rabbits. Test compound is administered byinfusion directly into the brain with the cannula delivering thecompound placed directly into the 4th ventrical of the brain. Severaldoses are tested for cardiovascular effects, including effects on bloodpressure and heart rate, following direct brain infusion. The bloodpressure effects following intravenous and ventricular infusion providesthe effect of the compound on the peripheral and central nervous systemsrespectively.

Example B8 Renal Effects of Test Compound in Conscious Rabbits

The long duration of blood pressure effect of a test compounds of theinvention results in a reduction in blood volume that can result fromdiueresis and/or the movement of fluid from the vascular space to theextravascular space. The effect of test compound on hematocrit levels ismeasured, compounds that reduce blood volume increase hematocrit.Characterization of the effect of α_(2B) antagonists on renal functionis determined by measuring urine volume, urine sodium and urinepotassium using methods described by Burke et al. (Effects of chronicsympatho-inhibition on renal excretory function in renovascularhypertension Sandra L. Burke, Roger G. Evans and Geoffrey A. Head.Journal of Hypertens 29:945-952 (2011).

Example B9 Human Clinical Studies

The compound is studied in a clinical trial of hypertensive patients whohave not reached their blood pressure goals on current therapy. Thetarget patient population are patients with refractory hypertension thathave not reached their blood pressure goals despite use of at least 3different blood pressure agents. The study compares the active compoundagainst a matched placebo compound with the primary objective ofcomparing mean blood pressure change from baseline to the end of thestudy between the active compound and placebo.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1: A method of lowering blood pressure in an individual in need thereofcomprising administering to the individual an effective amount of acompound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4),(C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate orN-oxide thereof: wherein

wherein for formula (A1) or (A2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino,aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(2a) and R^(4a) are taken together to form a methylene (—CH₂—) moietyor an ethylene (—CH₂CH₂—) moiety; each R^(3a) and R^(3b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) andR^(3b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(3a) and R¹ aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(3a) and R^(2a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(3a) and R^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; R⁵ is H or unsubstituted C₁-C₈ alkyl;each X¹, X² and X³ is independently N, CH or CR⁶; each m, n, o and p isindependently 0 or 1; each R⁶ is independently hydroxyl, nitro, cyano,halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h), where present, is independently H, hydroxyl,alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl,substituted or unsubstituted amino, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (A3) or (A4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; R⁵ is H or unsubstitutedC₁-C₈ alkyl; each m, n, o and p is independently 0 or 1; each X¹, X² andX³ is independently N, CH or CR⁶; each R⁶ is independently hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, alkoxy, acyloxy,thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted orunsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (B1) or (B2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy,acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(2a) andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl,cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are taken together withthe carbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR^(3a) and R^(2a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro,substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; each m, n, or o is independently 0 or1; each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro,cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R^(7g)are taken together to form a bond; each m, n and o is independently 0 or1; each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ isCR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O,S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d); Y², wherepresent, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y²is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, wherepresent, is CR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O,S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y²is CR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (B3) or (B4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R^(7g)are taken together to form a bond; each m, n and o is independently 0 or1; each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ isCR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O,S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d); Y², wherepresent, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y²is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, wherepresent, is CR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O,S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y²is CR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h): Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a) are taken together to form a bond,or R^(7c) and R^(7e), where present, are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f),where present, are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7e) and R^(7c) are takentogether to form a bond, or R^(7e) and R^(7g), where present, are takentogether to form a bond; each R^(7g) and R^(7h), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (C1) or (C2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and a vicinal R^(8(a-h)) are takentogether to form a bond; each R^(3a) and R^(3b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy,nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ and avicinal R^(8(a-h)) are taken together to form a bond; R⁵ is H orunsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independently N, CHor CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R², where present, to form a bond, or is takentogether with vicinal R⁴, where present, to form a bond; and Q issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety; or

wherein for formula (C3) or (C4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and avicinal R^(8a), where present, are taken together to form a bond; R⁵ isH or unsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independentlyN, CH or CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R⁴ to form a bond; and Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is agroup of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or asubstituted or unsubstituted C₁-C₈ alkyl and R^(10a) and R^(10b) aretaken together with the carbon to which they are attached to form asubstituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclylmoiety; Or

wherein for formula (D1) or (D2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and R^(7a) are taken together to forma bond; each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro,substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R² are taken together to form a bond, orR^(7a) and R⁴ are taken together to form a bond; each R^(7c) and R^(7d),where present, is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7c) and R^(7d) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7c) and R^(7a), where present,are taken together to form a bond, or R^(7c) and R^(7e) are takentogether to form a bond; each R^(7e) and R^(7f), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (D3) or (D4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R⁴ are taken together to form a bond; eachR^(7c) and R^(7d), where present, is independently H, hydroxyl, halo,nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a) where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. 2: Themethod of claim 1, wherein the individual has high blood pressure. 3:The method of claim 2, wherein the method reduces systolic bloodpressure of the individual. 4: The method of claim 2, wherein the methodreduces diastolic blood pressure of the individual. 5: The method ofclaim 2, wherein the method reduces (i) mean arterial blood pressure, or(ii) pulse pressure, of the individual. 6: The method of claim 3,wherein the method does not substantially increase heart rate of theindividual. 7: The method of claim 1, wherein the individual has one ormore risk factors for developing high blood pressure. 8: A method of (i)increasing renal blood flow, and/or (ii) decreasing sodium reabsorption,in an individual in need thereof comprising administering to theindividual an effective amount of a compound of the formulae (A1), (A2),(A3), (A4), (B1), (B2), (B3), (B4), (C1), (C2), (C3), (C4), (D1), (D2),(D3), or (D4); or a salt, solvate or N-oxide thereof: wherein

wherein for formula (A1) or (A2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino,aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(2a) and R^(4a) are taken together to form a methylene (—CH₂—) moietyor an ethylene (—CH₂CH₂—) moiety; each R^(3a) and R^(3b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) andR^(3b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(3a) and R¹ aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(3a) and R^(2a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(3a) and R^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; R⁵ is H or unsubstituted C₁-C₈ alkyl;each X¹, X² and X³ is independently N, CH or CR⁶; each m, n, o and p isindependently 0 or 1; each R⁶ is independently hydroxyl, nitro, cyano,halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h), where present, is independently H, hydroxyl,alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl,substituted or unsubstituted amino, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (A3) or (A4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; R⁵ is H or unsubstitutedC₁-C₈ alkyl; each m, n, o and p is independently 0 or 1; each X¹, X² andX³ is independently N, CH or CR⁶; each R⁶ is independently hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, alkoxy, acyloxy,thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted orunsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (B1) or (B2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy,acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(2a) andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl,cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are taken together withthe carbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR^(3a) and R^(2a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro,substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; each m, n, or o is independently 0 or1; each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro,cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R⁷⁹ aretaken together to form a bond; each m, n and o is independently 0 or 1;each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b),NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂,then Y², where present, is CR^(7c)R^(7d); Y², where present, isCR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O,S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, where present, isCR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) orSO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² isCR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (B3) or (B4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R^(7g)are taken together to form a bond; each m, n and o is independently 0 or1; each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ isCR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O,S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d); Y², wherepresent, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y²is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, wherepresent, is CR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O,S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y²is CR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a) are taken together to form a bond,or R^(7c) and R^(7e), where present, are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f),where present, are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7e) and R^(7c) are takentogether to form a bond, or R^(7e) and R^(7g), where present, are takentogether to form a bond; each R^(7g) and R^(7h), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (C1) or (C2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and a vicinal R^(8(a-h)) are takentogether to form a bond; each R^(3a) and R^(3b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy,nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ and avicinal R^(8(a-h)) are taken together to form a bond; R⁵ is H orunsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independently N, CHor CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R², where present, to form a bond, or is takentogether with vicinal R⁴, where present, to form a bond; and Q issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety; or

wherein for formula (C3) or (C4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and avicinal R^(8a), where present, are taken together to form a bond; R⁵ isH or unsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independentlyN, CH or CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R⁴ to form a bond; and Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is agroup of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or asubstituted or unsubstituted C₁-C₈ alkyl and R^(10a) and R^(10b) aretaken together with the carbon to which they are attached to form asubstituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclylmoiety; or

wherein for formula (D1) or (D2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and R^(7a) are taken together to forma bond; each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro,substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R² are taken together to form a bond, orR^(7a) and R⁴ are taken together to form a bond; each R^(7c) and R^(7d),where present, is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7c) and R^(7d) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7c) and R^(7a) where present,are taken together to form a bond, or R^(7c) and R^(7e) are takentogether to form a bond; each R^(7e) and R^(7f), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (D3) or (D4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R⁴ are taken together to form a bond; eachR^(7c) and R^(7d), where present, is independently H, hydroxyl, halo,nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. 9: Themethod of claim 8, wherein the method results in increase in renal bloodflow. 10: The method of claim 8, wherein the method results in decreasein sodium reabsorption. 11: The method of claim 9, wherein the methodresults in increase in urine sodium content and/or increase in urinevolume. 12: The method of claim 9, wherein the method results in any oneor more of: (i) reducing edema, (ii) reducing elevated blood ureanitrogen to creatinine (BUN/Cr) ratio, and (iii) decreasing creatininelevels. 13: The method of claim 1, wherein the individual has or is atrisk of developing acute or chronic congestive heart failure, acutedecompensated congestive heart failure, acute or chronic renal failure,or acute or chronic renal failure due to renal insufficiency. 14: Amethod of treating a disease or condition that is responsive to any oneor more of: (i) a decrease in blood pressure; (ii) an increase in renalblood flow; and (iii) a decrease of sodium reabsorption, comprisingadministering to an individual in need thereof an effective amount of acompound of the formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4),(C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate orN-oxide thereof: wherein

wherein for formula (A1) or (A2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino,aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(2a) and R^(4a) are taken together to form a methylene (—CH₂—) moietyor an ethylene (—CH₂CH₂—) moiety; each R^(3a) and R^(3b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) andR^(3b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(3a) and R¹ aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(3a) and R^(2a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(3a) and R^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; R⁵ is H or unsubstituted C₁-C₈ alkyl;each X¹, X² and X³ is independently N, CH or CR⁶; each m, n, o and p isindependently 0 or 1; each R⁶ is independently hydroxyl, nitro, cyano,halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h), where present, is independently H, hydroxyl,alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl,substituted or unsubstituted amino, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (A3) or (A4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; R⁵ is H or unsubstitutedC₁-C₈ alkyl; each m, n, o and p is independently 0 or 1; each X¹, X² andX³ is independently N, CH or CR⁶; each R⁶ is independently hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, alkoxy, acyloxy,thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted orunsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (B1) or (B2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy,acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(2a) andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl,cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are taken together withthe carbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR^(3a) and R^(2a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro,substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; each m, n, or o is independently 0 or1; each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro,cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R^(7g)are taken together to form a bond; each m, n and o is independently 0 or1; each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ isCR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O,S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d); Y², wherepresent, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y²is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, wherepresent, is CR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O,S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y²is CR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (B3) or (B4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R^(7g)are taken together to form a bond; each m, n and o is independently 0 or1; each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ isCR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O,S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d); Y², wherepresent, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y²is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, wherepresent, is CR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O,S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y²is CR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a) are taken together to form a bond,or R^(7c) and R^(7e), where present, are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f),where present, are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7e) and R^(7c) are takentogether to form a bond, or R^(7e) and R^(7g), where present, are takentogether to form a bond; each R^(7g) and R^(7h), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (C1) or (C2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and a vicinal R^(8(a-h)) are takentogether to form a bond; each R^(3a) and R^(3b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy,nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ and avicinal R^(8(a-h)) are taken together to form a bond; R⁵ is H orunsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independently N, CHor CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R², where present, to form a bond, or is takentogether with vicinal R⁴, where present, to form a bond; and Q issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety; or

wherein for formula (C3) or (C4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and avicinal R^(8a), where present, are taken together to form a bond; R⁵ isH or unsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independentlyN, CH or CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R⁴ to form a bond; and Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is agroup of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or asubstituted or unsubstituted C₁-C₈ alkyl and R^(10a) and R^(10b) aretaken together with the carbon to which they are attached to form asubstituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclylmoiety; or

wherein for formula (D1) or (D2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and R^(7a) are taken together to forma bond; each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro,substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R² are taken together to form a bond, orR^(7a) and R⁴ are taken together to form a bond; each R^(7c) and R^(7d),where present, is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7c) and R^(7d) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7c) and R^(7a) where present,are taken together to form a bond, or R^(7c) and R^(7e) are takentogether to form a bond; each R^(7e) and R^(7f), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (D3) or (D4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R⁴ are taken together to form a bond; eachR^(7c) and R^(7d), where present, is independently H, hydroxyl, halo,nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy. 15:The method of claim 14, wherein the disease or condition ishypertension. 16: The method of claim 15, wherein the disease orcondition is treatment-resistant hypertension. 17: The method of claim14, wherein the disease or condition is hypertensive emergency. 18: Themethod of claim 14, wherein the disease or condition is a cardiac orrenal disease or condition. 19: The method of claim 1, wherein thecompound is an adrenergic receptor α_(2B) antagonist. 20: The method ofclaim 19, wherein the compound is also an adrenergic receptor α_(1B)antagonist. 21: The method of claim 19, wherein the compound is also anadrenergic receptor α_(1D) antagonist. 22: A kit comprising (i) acompound of formulae (A1), (A2), (A3), (A4), (B1), (B2), (B3), (B4),(C1), (C2), (C3), (C4), (D1), (D2), (D3), or (D4); or a salt, solvate orN-oxide thereof, or a pharmaceutically acceptable salt thereof, and (ii)instructions for use according to the method of claim 1; and whereinwherein

wherein for formula (A1) or (A2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino,aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) aretaken together with the carbon to which they are attached to form acarbonyl moiety or a cycloalkyl moiety, or R^(2a) and R¹ are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(2a) and R^(4a) are taken together to form a methylene (—CH₂—) moietyor an ethylene (—CH₂CH₂—) moiety; each R^(3a) and R^(3b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) andR^(3b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(3a) and R¹ aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R^(3a) and R^(2a) are taken together to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, orR^(3a) and R^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; R⁵ is H or unsubstituted C₁-C₈ alkyl;each X¹, X² and X³ is independently N, CH or CR⁶; each m, n, o and p isindependently 0 or 1; each R⁶ is independently hydroxyl, nitro, cyano,halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h), where present, is independently H, hydroxyl,alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl,substituted or unsubstituted amino, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (A3) or (A4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; R⁵ is H or unsubstitutedC₁-C₈ alkyl; each m, n, o and p is independently 0 or 1; each X¹, X² andX³ is independently N, CH or CR⁶; each R⁶ is independently hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, alkoxy, acyloxy,thiol, —S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂-aralkyl, substituted orunsubstituted amino, halo, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than hydroxyland thiol and thiol; and Q is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedamino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano,alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; or

wherein for formula (B1) or (B2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; each R^(2a) and R^(2b) is independentlyH, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl,alkoxy, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy,acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a carbonyl moiety or a cycloalkyl moiety, or R^(2a) andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R^(3a) are takentogether to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl,cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are taken together withthe carbon to which they are attached to form a carbonyl moiety or acycloalkyl moiety, or R^(3a) and R¹ are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR^(3a) and R^(2a) are taken together to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; each R^(4a) and R^(4b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitro,substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy,acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) andR^(4b) are taken together with the carbon to which they are attached toform a carbonyl moiety or a cycloalkyl moiety, or R^(4a) and R¹ aretaken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(3a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; each m, n, or o is independently 0 or1; each R^(5a) and R^(5b) is independently H, hydroxyl, halo, nitro,cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R^(7g)are taken together to form a bond; each m, n and o is independently 0 or1; each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ isCR^(7a)R^(7b), NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O,S, S(O) or SO₂, then Y², where present, is CR^(7c)R^(7d); Y², wherepresent, is CR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y²is NR⁸, O, S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, wherepresent, is CR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O,S, S(O) or SO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y²is CR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (B3) or (B4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together withthe carbon to which it is attached and a geminal R², R³, R⁴ or R¹⁰ toform a carbonyl moiety or a cycloalkyl moiety; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m, n and o are each 0, then R^(5a) and R^(7a)are taken together to form a bond, or when m is 1, and n and o are each0, then R^(5a) and R^(7c) are taken together to form a bond, or when mand n are each 1, and o is 0, then R^(5a) and R^(7e) are taken togetherto form a bond, or when m, n and o are each 1, then R^(5a) and R⁷⁹ aretaken together to form a bond; each m, n and o is independently 0 or 1;each X¹, X² and X³ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b),NR⁸, O, S, S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂,then Y², where present, is CR^(7c)R^(7d); Y², where present, isCR^(7c)R^(7d), NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O,S, S(O) or SO₂, then Y¹ is CR^(7a)R^(7b) and Y³, where present, isCR^(7e)R^(7f); Y³, where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) orSO₂, provided that when Y³ is NR⁸, O, S, S(O) or SO₂, then Y² isCR^(7c)R^(7d) and Y⁴, where present, is CR^(7g)R^(7h); Y⁴, wherepresent, is CR^(7g)R^(7h), NR⁸, O, S, S(O) or SO₂, provided that when Y⁴is NR⁸, O, S, S(O) or SO₂, then Y³ is CR^(7e)R^(7f); each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(7a) andR^(7b) is independently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond; each R^(7c) and R^(7d), where present, is independentlyH, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl,C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a) are taken together to form a bond,or R^(7c) and R^(7e), where present, are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f),where present, are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7e) and R^(7c) are takentogether to form a bond, or R^(7e) and R^(7g), where present, are takentogether to form a bond; each R^(7g) and R^(7h), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (C1) or (C2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and a vicinal R^(8(a-h)) are takentogether to form a bond; each R^(3a) and R^(3b) is independently H,substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy,nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ and avicinal R^(8(a-h)) are taken together to form a bond; R⁵ is H orunsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independently N, CHor CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R², where present, to form a bond, or is takentogether with vicinal R⁴, where present, to form a bond; and Q issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety; or

wherein for formula (C3) or (C4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ and avicinal R^(8a), where present, are taken together to form a bond; R⁵ isH or unsubstituted C₁-C₈ alkyl; each X¹, X², X³ and X⁴ is independentlyN, CH or CR⁶; each m, n, o and p is independently 0 or 1; each R⁶ isindependently hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkoxy, substituted orunsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl; each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —S(O)₂-alkyl,—S(O)₂-aryl, —S(O)₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol and thiol, or is takentogether with vicinal R⁴ to form a bond; and Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is agroup of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or asubstituted or unsubstituted C₁-C₈ alkyl and R^(10a) and R^(10b) aretaken together with the carbon to which they are attached to form asubstituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclylmoiety; or

wherein for formula (D1) or (D2): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R², where present, aretaken together to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(2a), where present, are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, orR¹ and R⁴, where present, are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety or R¹ and R^(4a),where present, are taken together to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each R², R^(2a) and R^(2b), wherepresent, is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstitutedamino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl,or R^(2a) and R^(2b) are taken together with the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or R² andR¹ are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R² and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R² and R⁴ are taken together to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety or R^(2a)and R⁴ are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R² and R^(7a) are taken together to forma bond; each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro,substituted or unsubstituted amino, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R² are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R⁴ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety or R^(3a) and R^(4a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; each R⁴ orR^(4a), where present, is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R⁴ and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) and R¹are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, or R⁴ and R^(2a) are taken together to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R⁴ and R^(3a) are taken together to forma propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,or R^(4a) and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R² are taken together to form a bond, orR^(7a) and R⁴ are taken together to form a bond; each R^(7c) and R^(7d),where present, is independently H, hydroxyl, halo, nitro, cyano,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstituted aryloxy,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl,acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl,aminocarbonylamino, aminocarbonylalkoxy aminosulfonyl, sulfonylamino, orR^(7c) and R^(7d) are taken together with the carbon to which they areattached to form a carbonyl moiety, or R^(7c) and R^(7a) where present,are taken together to form a bond, or R^(7c) and R^(7e) are takentogether to form a bond; each R^(7e) and R^(7f), where present, isindependently H, hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; or

wherein for formula (D3) or (D4): R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b), R^(3a), R^(3b),R^(10a) and R^(10b) is independently H, hydroxyl, nitro, cyano, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl,acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl, C₁-C₈perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³ or R¹⁰ to form a carbonyl moiety or acycloalkyl moiety; R⁴ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or R⁴ andR^(7a) are taken together to form a bond; each m, n and o isindependently 0 or 1; each R^(5a) and R^(5b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(5a) and R^(5b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or when m-o are each 0, then R^(5a) and R^(7a) aretaken together to form a bond, or when m is 1, and n-o are each 0, thenR^(5a) and R^(7c) are taken together to form a bond, or when m-n areeach 1, and o is 0, then R^(5a) and R^(7e) are taken together to form abond, or when m-o are each 1, then R^(5a) and R^(7g) are taken togetherto form a bond; each m, n and o is independently 0 or 1; each X¹, X², X³and X⁴ is independently N, CH or CR⁶; Y¹ is CR^(7a)R^(7b), NR⁸, O, S,S(O) or SO₂, provided that when Y¹ is NR⁸, O, S, S(O) or SO₂, then Y²,where present, is CR^(7c)R^(7d); Y², where present, is CR^(7c)R^(7d),NR⁸, O, S, S(O) or SO₂, provided that when Y² is NR⁸, O, S, S(O) or SO₂,then Y¹ is CR^(7a)R^(7b) and Y³, where present, is CR^(7e)R^(7f); Y³,where present, is CR^(7e)R^(7f), NR⁸, O, S, S(O) or SO₂, provided thatwhen Y³ is NR⁸, O, S, S(O) or SO₂, then Y² is CR^(7c)R^(7d) and Y⁴,where present, is CR^(7g)R^(7h); Y⁴, where present, is CR^(7g)R^(7h),NR⁸, O, S, S(O) or SO₂, provided that when Y⁴ is NR⁸, O, S, S(O) or SO₂,then Y³ is CR^(7e)R^(7f); each R⁶ is independently hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₁-C₈ alkoxy, substituted or unsubstitutedaryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,—S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted or unsubstitutedamino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(7a) and R^(7b) is independently H,hydroxyl, halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7a) and R^(7b)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7a) and R^(7c), where present, are taken togetherto form a bond, or R^(7a) and R⁴ are taken together to form a bond; eachR^(7c) and R^(7d), where present, is independently H, hydroxyl, halo,nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted aryloxy, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, substituted orunsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7c) and R^(7d)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7c) and R^(7a), where present, are taken togetherto form a bond, or R^(7c) and R^(7e) are taken together to form a bond;each R^(7e) and R^(7f), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7e) and R^(7f)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7e) and R^(7c) are taken together to form a bond,or R^(7e) and R^(7g), where present, are taken together to form a bond;each R^(7g) and R^(7h), where present, is independently H, hydroxyl,halo, nitro, cyano, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₁-C₈ alkoxy, C₁-C₈ perhaloalkyl, C₁-C₈perhaloalkoxy, substituted or unsubstituted C₂-C₈ alkenyl, substitutedor unsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted aryloxy, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy,carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy aminosulfonyl, sulfonylamino, or R^(7g) and R^(7h)are taken together with the carbon to which they are attached to form acarbonyl moiety, or R^(7g) and R^(7e) are taken together to form a bond,or R^(7g) and R^(5a) are taken together to form a bond; and R⁸ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thioalkyl, —S(O)-alkyl,—S(O)-aryl, —S(O)-aralkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy.